Archive for January, 2021

ROCKVILLE, Md., Jan. 5, 2021 /PRNewswire/ --REGENXBIO Inc. (Nasdaq: RGNX) today provided an update on the RGX-314 programs, including the announcement that the pivotal program for RGX-314 for the treatment of wet age-related macular degeneration (wet AMD) is now active. In addition, REGENXBIO announced a new program, RGX-202, a novel, potentially best-in-class, one-time gene therapy for the treatment of Duchenne Muscular Dystrophy (DMD).

"2020 was a very productive year at REGENXBIO, and we are excited to move into 2021, which we expect to be another year of clinical execution. The initiation of our first pivotal program for RGX-314 for the treatment of wet AMD is a great step forward for the field as we look to broaden the applicability of gene therapy to larger patient populations. In addition, we are excited to announce RGX-202, a potential one-time gene therapy for the treatment of DMD. RGX-202 is the first gene therapy program in the REGENXBIO pipeline to be developed under the leadership of our Chief Scientific Officer, Olivier Danos. We look forward to filing an IND for this program later this year," said Kenneth T. Mills, President and Chief Executive Officer of REGENXBIO. "We continue to advance our pipeline of innovative therapies in the clinic as well as our manufacturing capabilities. I would also like to express my deep gratitude to our employees and clinical partners as well as patients and their families for their ongoing commitment and support despite the challenges posed by the global COVID-19 pandemic."

Pivotal Program for RGX-314 for the Treatment of wet AMD

REGENXBIO today announced that ATMOSPHERE, the first of two planned pivotal trials to evaluate RGX-314, is active and patient screening is ongoing. RGX-314 is a potential best-in-class, one-time gene therapy for the treatment of wet AMD.

REGENXBIO completed an End of Phase 2 meeting with the FDA to discuss the details of a pivotal program to support a Biologics License Application (BLA). Based on discussions with the FDA, REGENXBIO plans to conduct two randomized, well-controlled clinical trials to evaluate the efficacy and safety of RGX-314 in patients with wet AMD, enrolling approximately 700 patients total. In addition, REGENXBIO and the FDA aligned on a clear path to support manufacturing plans in the pivotal program. REGENXBIO expects to submit a BLA based on these trials in 2024.

"We are pleased to have reached alignment with the FDA on key elements of our pivotal program for the treatment of wet AMD. Our plan allows us to further accelerate the clinical development of RGX-314 towards the goal of a BLA filing in 2024 and we have already begun site activation and patient screening for our first planned pivotal trial," said Steve Pakola, M.D., Chief Medical Officer of REGENXBIO. "We have strengthened the key design elements for the planned trials based on the long-term data from our dose-escalation Phase I/IIa trial of RGX-314 and believe that we are well-positioned to execute on this pivotal program."

Suprachoroidal Delivery of RGX-314 for the Treatment of Wet AMD and Diabetic Retinopathy (DR)

New Program for the Treatment of Duchenne Muscular Dystrophy

REGENXBIO also announced today the development of a potential one-time gene therapy for the treatment of DMD, which is based on a novel microdystrophin construct.

"DMD is a severe, degenerative disease affecting thousands of children worldwide. It is caused by mutations of the gene which encodes dystrophin, a protein necessary for muscle cell strength and function, and innovation and development of potential new treatment options for patients with DMD has been a goal for the gene therapy field for many years," said Olivier Danos, Ph.D., Chief Scientific Officer of REGENXBIO. "Since I joined REGENXBIO, we have been working to develop this gene therapy candidate using our proprietary AAV8 vector, with a focus on including the C-Terminal Domain of dystrophin, which may potentially bolster the key cell signaling pathways and muscle membrane integrity, leading to improved muscle strength and resistance. We look forward to completing the IND-enabling studies and bringing this program into the clinic."

The design of the new RGX-202 microdystrophin transgene is based on innovative vector engineering by REGENXBIO scientists and incorporates learnings from the laboratory of George Dickson, Emeritus Professor of Molecular Cell Biology at Royal Holloway, University of London, a pioneering figure in dystrophin research.

"The data from dystrophic laboratory trials suggest that a gene therapy delivering a microdystrophin gene incorporating an extended coding region from the C-Terminal Domain such as RGX-202 may provide substantial added muscle function for patients with DMD. A blend of the innovative science applied to microdystrophin gene design, and an AAV vector that is well-established, makes this new approach very promising," said Professor George Dickson from Royal Holloway. "I am pleased to see this important science developing from Royal Holloway's research is now being advanced under the leadership and gene therapy expertise of Olivier Danos and the team from REGENXBIO. I look forward to seeing this program enter the clinic."

Financial Guidance

REGENXBIO expects to report that as of December 31, 2020, it had between $515 million and $530 million in cash, cash equivalents and marketable securities, including the $200 million upfront payment from REGENXBIO's royalty monetization agreement with entities managed by Healthcare Royalty Management, LLC. REGENXBIO expects these resources to fund its operations, including the completion of its internal manufacturing capabilities and clinical advancement of its product candidates, until late 2022.

About REGENXBIO Inc.

REGENXBIO is a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy. REGENXBIO's NAV Technology Platform, a proprietary adeno-associated virus (AAV) gene delivery platform, consists of exclusive rights to more than 100 novel AAV vectors, including AAV7, AAV8, AAV9 and AAVrh10. REGENXBIO and its third-party NAV Technology Platform Licensees are applying the NAV Technology Platform in the development of a broad pipeline of candidates in multiple therapeutic areas.

About Wet AMD

Wet AMD is characterized by loss of vision due to new, leaky blood vessel formation in the retina. Wet AMD is a significant cause of vision loss in the United States, Europe and Japan, with up to 2 million people living with wet AMD in these geographies alone. Current anti-VEGF therapies have significantly changed the landscape for treatment of wet AMD, becoming the standard of care due to their ability to prevent progression of vision loss in the majority of patients. These therapies, however, require life-long intraocular injections, typically repeated every four to 12 weeks in frequency, to maintain efficacy. Due to the burden of treatment, patients often experience a decline in vision with reduced frequency of treatment over time.

About RGX-314

RGX-314 is being developed as a potential one-time treatment for wet AMD, diabetic retinopathy, and other chronic retinal conditions. RGX-314 consists of the NAV AAV8 vector, which encodes an antibody fragment designed to inhibit vascular endothelial growth factor (VEGF). RGX-314 is believed to inhibit the VEGF pathway by which new, leaky blood vessels grow and contribute to the accumulation of fluid in the retina.

REGENXBIO is advancing two separate routes of administration of RGX-314 to the eye, through a standardized subretinal delivery procedure as well as delivery to the suprachoroidal space. REGENXBIO has licensed certain exclusive rights to the SCS Microinjector from Clearside Biomedical, Inc. to deliver gene therapy treatments to the suprachoroidal space of the eye.

About ATMOSPHERE

ATMOSPHERE is a multi-center, randomized, active-controlled trial to evaluate the efficacy and safety of a single-administration of RGX-314 versus standard of care in patients with wet AMD. The trial is designed to enroll 300 patients at a 1:1:1 ratio across two RGX-314 dose arms (6.4x1010 genome copies (GC)/eye and 1.3x1011 GC/eye delivered subretinally) and an active control arm of monthly intravitreal injections of ranibizumab (0.5 mg/eye). The primary endpoint of the trial is non-inferiority to ranibizumab based on change from baseline in Best Corrected Visual Acuity (BCVA) at 54 weeks. Secondary endpoints of the trial include safety and tolerability, change in central retinal thickness (CRT) and need for supplemental anti-VEGF injections. Patient selection criteria will include patients with wet AMD who are responsive to anti-VEGF treatment and will be independent of preexisting neutralizing antibody status. Patients will not receive prophylactic immune suppressive corticosteroid therapy before or after administration of RGX-314. The trial will be conducted at approximately 60 clinical sites based in the United States, with over 100 retinal surgeons.

About AAVIATE

AAVIATE is a multi-center, open-label, randomized, active-controlled, dose-escalation trial that will evaluate the efficacy, safety and tolerability of suprachoroidal delivery of RGX-314 using the SCS Microinjector, a targeted, in-office route of administration. The trial is expected to enroll approximately 40 patients with severe wet AMD across two cohorts. Patients in each cohort will be randomized to receive RGX-314 versus monthly 0.5 mg ranibizumab intravitreal injection at a 3:1 ratio, and two dose levels of RGX-314 will be evaluated: 2.5x1011GC/eye and 5x1011GC/eye. Patients will not receive prophylactic immune suppressive corticosteroid therapy before or after administration of RGX-314. The primary endpoint of the trial is mean change in vision in patients dosed with RGX-314, as measured by best corrected visual acuity (BCVA), at Week 40 from baseline, compared to patients receiving monthly injections of ranibizumab. Other endpoints include mean change in central retinal thickness (CRT) and number of anti-VEGF intravitreal injections received following administration of RGX-314.

About ALTITUDE

ALTITUDE is a multi-center, open label, randomized, controlled dose-escalation trial that will evaluate the efficacy, safety and tolerability of suprachoroidal delivery of RGX-314. The trial is expected to enroll approximately 40 patients with DR across two cohorts. Patients will be randomized to receive RGX-314 versus observational control at a 3:1 ratio, and two dose levels of RGX-314 will be evaluated: 2.5x1011GC/eye and 5.0x1011GC/eye. Patients will not receive prophylactic immune suppressive corticosteroid therapy before or after administration of RGX-314. The primary endpoint of the trial is the proportion of patients that improve in DR severity based on the Early Treatment Diabetic Retinopathy Study-Diabetic Retinopathy Severity Scale (ETDRS-DRSS) at 48 weeks. Other endpoints include safety and development of DR-related ocular complications.

About Duchenne Muscular Dystrophy

DMD is a severe, progressive, degenerative muscle disease, affecting 1 in 3,500 to 5,000 boys born each year worldwide. DMD is caused by mutations in the DMD gene which encodes for dystrophin, a protein involved in muscle cell structure and signaling pathways. Without dystrophin, muscles throughout the body degenerate and become weak, eventually leading to loss of movement and independence, required support for breathing, cardiomyopathy and premature death.

About RGX-202

RGX-202 is designed to deliver a novel microdystrophin transgene which retains key elements of the dystrophin protein, including an extended coding region of the C-Terminal (CT) domain found in naturally-occurring dystrophin, as well as other fundamental improvements to the transgene. Presence of the CT domain has been shown to recruit several key proteins to the muscle cell membrane, leading to improved muscle resistance to contraction-induced muscle damage in dystrophic mice. Additional design features, including codon optimization and reduction of CpG content, may potentially improve gene expression, increase translational efficiency and reduce immunogenicity. RGX-202 is designed to use the NAV AAV8 vector, a vector used in numerous clinical trials, and a well-characterized muscle specific promoter (Spc5-12) to support the delivery and targeted expression of genes throughout skeletal and heart muscle.

Forward-Looking Statements

This press release includes "forward-looking statements," within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These statements express a belief, expectation or intention and are generally accompanied by words that convey projected future events or outcomes such as "believe," "may," "will," "estimate," "continue," "anticipate," "design," "intend," "expect," "could," "plan," "potential," "predict," "seek," "should," "would" or by variations of such words or by similar expressions. The forward-looking statements include statements relating to, among other things, REGENXBIO's future operations and clinical trials. REGENXBIO has based these forward-looking statements on its current expectations and assumptions and analyses made by REGENXBIO in light of its experience and its perception of historical trends, current conditions and expected future developments, as well as other factors REGENXBIO believes are appropriate under the circumstances. However, whether actual results and developments will conform with REGENXBIO's expectations and predictions is subject to a number of risks and uncertainties, including the timing of enrollment, commencement and completion and the success of clinical trials conducted by REGENXBIO, its licensees and its partners, the timing of commencement and completion and the success of preclinical studies conducted by REGENXBIO and its development partners, the timely development and launch of new products, the ability to obtain and maintain regulatory approval of product candidates, the ability to accurately predict how long REGENXBIO's existing cash resources will be sufficient to fund its anticipated operating expenses, the ability to obtain and maintain intellectual property protection for product candidates and technology, trends and challenges in the business and markets in which REGENXBIO operates, the size and growth of potential markets for product candidates and the ability to serve those markets, the rate and degree of acceptance of product candidates, the impact of the COVID-19 pandemic or similar public health crises on REGENXBIO's business, and other factors, many of which are beyond the control of REGENXBIO. Refer to the "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" sections of REGENXBIO's Annual Report on Form 10-K for the year ended December 31, 2019, and comparable "risk factors" sections of REGENXBIO's Quarterly Reports on Form 10-Q and other filings, which have been filed with the U.S. Securities and Exchange Commission (SEC) and are available on the SEC's website at http://www.sec.gov. All of the forward-looking statements made in this press release are expressly qualified by the cautionary statements contained or referred to herein. The actual results or developments anticipated may not be realized or, even if substantially realized, they may not have the expected consequences to or effects on REGENXBIO or its businesses or operations. Such statements are not guarantees of future performance and actual results or developments may differ materially from those projected in the forward-looking statements. Readers are cautioned not to rely too heavily on the forward-looking statements contained in this press release. These forward-looking statements speak only as of the date of this press release. REGENXBIO does not undertake any obligation, and specifically declines any obligation, to update or revise any forward-looking statements,whether as a result of new information, future events or otherwise.

SCS Microinjector is a trademark of Clearside Biomedical, Inc. All other trademarks referenced herein are registered trademarks of REGENXBIO.

Preliminary Financial Information

REGENXBIO reports its financial results in accordance with U.S. generally accepted accounting principles. All financial data in this press release for the year ended December 31, 2020 is preliminary, as financial close procedures for the year ended December 31, 2020 are not yet complete. These estimates are not a comprehensive statement of the financial position of REGENXBIO for the year ended December 31, 2020. Actual results may differ materially from these estimates as a result of the completion of normal year-end accounting procedures and adjustments, including the execution of REGENXBIO's internal control over financial reporting, the completion of the preparation and management's review of REGENXBIO's financial statements for the year ended December 31, 2020 and the subsequent occurrence or identification of events prior to the filing of the financial results for the year ended December 31, 2020 on Form 10-K with the SEC.

Contacts:

Tricia TruehartInvestor Relations and Corporate Communications347-926-7709[emailprotected]

Investors:Eleanor Barisser, 212-600-1902[emailprotected]

Media:David Rosen, 212-600-1902[emailprotected]

1Koo, Taeyoung et al. "Delivery of AAV2/9-microdystrophin genes incorporating helix 1 of the coiled-coil motif in the C-terminal domain of dystrophin improves muscle pathology and restores the level of 1-syntrophin and -dystrobrevin in skeletal muscles of mdx mice." Human gene therapy vol. 22,11 (2011): 1379-88. doi:10.1089/hum.2011.020

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REGENXBIO Announces Update on RGX-314 and Pivotal Program for the Treatment of Wet AMD and New Gene Therapy Program for the Treatment of Duchenne...

INTRODUCTION

Tuberous sclerosis complex (TSC) is a hereditary disease affecting multiple organs with an incidence of about 1 of 5500 (1, 2), resulting from mutations in either TSC1 encoding hamartin or TSC2 encoding tuberin. Hamartin and tuberin normally act as a complex to inhibit mTORC1 (mammalian/mechanistic target of rapamycin complex 1) through guanosine triphosphatase (GTPase) activating effects on Ras homolog enriched in brain (Rheb) (3). When a mutation in the corresponding normal TSC1 or TSC2 allele occurs somatically in susceptible cells, they enlarge and proliferate causing abnormal development and tissue lesions. These secondary mutations can occur prenatally or after birth in different cell types, and the timing and frequency of these hits affect the severity of the disease in a stochastic manner. Neurodevelopmental manifestations are responsible for the greatest morbidity, including severe, refractory epilepsy and hydrocephalus, as well as autism (40%), cognitive impairment (50%), and mental health issues (70%) (46). In addition, renal angiomyolipomas forming later in life can cause life-threatening hemorrhage and/or renal failure, and pulmonary lymphangioleiomyomatosis can severely compromise respiratory function. Current treatments include surgical resection and/or treatment with rapamycin analogs (rapalogs). Although often well tolerated, rapalogs cause immune suppression (7) and potentially compromise early brain development (8), and lifelong therapy is often required. Therefore, there is a clear need to identify other therapeutic approaches for TSC.

Adeno-associated virus (AAV) vectors have been used widely in clinical trials for many hereditary diseases with little-to-no toxicity, long-term action in nondividing cells, and improvement in symptoms (911). Benefit can be seen after a single injection and some serotypes, e.g., AAV9, AAVrh8, and AAVrh10, can efficiently enter the brain, as well as peripheral organs after intravenous (IV) injection (12, 13). The insert capacity of AAV vectors is about 4.7 kb (including promoter, transgene, polyadenylation (poly A) sequence, and other regulatory elements), and the complementary DNA (cDNA) for tuberin (5.4 kb) cannot be accommodated. We generated a cDNA encoding a shorter form of tuberin, termed cTuberin. We tested its lack of toxicity and ability to bind to hamartin and Rheb1, as well as to suppress phosphoS6 kinase activity in cultured cells. In a stochastic mouse model of TSC2 [based on a TSC1 model; (14)], AAV vector encoding Cre recombinase was introduced by intracerebroventricular (ICV) injection into homozygous Tsc2-floxed mice (15) at postnatal day 0 (P0) typically leading to death at about P58 with enlarged ventricles. Near-normal life span and reduction of brain pathology were achieved in most of these animals by a single IV injection of an AAV9 vector encoding cTuberin under a strong, constitutive promoter. These studies demonstrate the ability of cTuberin to suppress overgrowth of tuberin-null cells, including neural cells and, presumably, other cells in the body, and, hence, support the preclinical efficacy of AAV-cTuberin for TSC2 lesions.

Whereas hamartin is encoded in a cDNA of 3.5 kb, which fits into an AAV vector (16), the cDNA for tuberin (5.4 kb) is too large. To generate a potentially functional form of tuberin encoded in a shorter cDNA, we retained the N-terminal domain that binds to hamartin and the C-terminal domain containing GAP (GTPase-activating protein) activity that inhibits Rheb, with N-terminal region and phosphorylation of the C-terminal region of tuberin also thought to regulate formation of the complex with hamartin Fig. 1A (3, 1720). The potential for cTuberin to retain some functional activity was supported by findings of Momose et al. (21) that genomic overexpression of the C-terminal region of rat tuberin (amino acids 1425 to 1755) can suppress renal tumors in the Tsc2 Eker rat model. We felt it was also important to retain the hamartin-binding domain at the N terminus, as hamartin and tuberin function together as a complex with Tre2-Bub2-Cdc16 (TBC) 1 domain family, member 7 (TBC1D7) to accelerate guanosine triphosphate (GTP) to guanosine diphosphate conversion of Rheb-GTP (3, 22). In addition, this requirement for complex formation for activity might act to limit potential negative effects of high levels of transgenic cTuberin expression. cTuberin was thus designed to retain key elements of function, including 450 amino acids from the N-terminal region and 292 amino acids from the C-terminal region, joined by a flexible serine-glycine linker of 16 amino acids (fig. S1). This cDNA, with a Kozak sequence, and a C-terminal c-Myc tag was inserted into an AAV2 backbone under a chicken -actin (CBA) promoter (23), with a WPRE (woodchuck hepatitis virus posttranscriptional regulatory element) and poly A signals (Fig. 1B).

(A) The functional domains of tuberin are depicted with numbers representing amino acid residues for the full-length human proteins [based on (3)]. T1BD, hamartin-binding domain; GAP, GAP domain homologous with that in Rap1GAP. cTuberin contains the T1BD and GAP domains of TSC2 with a glycine-serine linker and C-terminal c-Myc tag. (B) Schematic of AAV-cTuberin transgene expression cassette. ITR, inverted terminal repeats; CBA, chicken -actin promoter; WPRE, woodchuck hepatitis virus posttranscriptional regulatory element; pA, poly A signal sequences [from SV40 and bovine growth hormone (BGH)].

Human embryonic kidney (HEK) 293T cells were transfected with plasmids for empty AAV (AAV1-null that contains all the elements except the cTuberin cDNA), AAV-CBAgreen fluorescent protein (GFP), or AAV-CBA-cTuberin-Myc to assess the expression level of cTuberin. In addition to endogenously expressed tuberin (200 kDa), cTuberin expression at the appropriate molecular weight (MW) of 85 kDa was detected on Western blots using anti-tuberin and anti-Myc antibodies (Fig. 2A; representative blot, n = 3) Immunocytochemistry of 293T cells transfected with different plasmids demonstrated stronger tuberin immunoreactivity in those transfected with AAV-CBA-cTuberin-Myc compared to other groups that expressed only endogenous tuberin (Fig. 2B; representative micrographs, n = 3). We determined transfection efficiency of these cells in two waysmicroscopically and by flow cytometry. As it is challenging to differentiate expression of endogenous tuberin from cTuberin, image analysis was carried out microscopically for each well (approximately 2000 cells per well; n = 3) for 4,6-diamidino-2-phenylindole (DAPI)positive and c-Mycpositive cells, and we determined that 43 2% of cells were transfected with the AAV-CBA-cTuberin-Myc (Fig. 2B). Cytotoxicity assays were also performed following transfection of HEK293T cells with AAV-null, AAV-CBA-GFP, or AAV-CBA-cTuberin-Myc plasmids to evaluate potential toxicity of cTuberin. The lactate dehydrogenase (LDH) assay (Dojindo Molecular Technologies Inc., Rockville, MD, USA) revealed no cytotoxicity in cTuberin-transfected cells, as compared to controls (Fig. 2C; n = 3). As a second way to evaluate the extent of transfection of these 293T cells with AAV-CBA-cTuberin-Myc plasmid DNA (n = 3), we sorted the c-Mycpositive cells using flow cytometry, after staining the cells with unlabeled c-Myc primary antibody followed by Alexa Fluor 647conjugated secondary antibody. Compared to the background in nontransfected cells (4 1%), we detected a marked increase of c-Mycpositive cells (50 1% or 46% minus the background, similar to the 43% determined by cell counting) after transfection with the AAV-CBA-cTuberin-Myc plasmid (P < 0.0001) (Fig. 2D). This suggests that the apparently endogenous levels of cTuberin reflect 43 to 46% transfection efficiency and that levels of cTuberin are about twice as high as endogenous tuberin in these transfected cells, without apparent toxicity.

(A) HEK293T cells were transfected with empty AAV (AAV-null), AAV-CBA-GFP, or AAV-cTuberin-Myc (AAV-CBA-cTub-Myc) plasmids. Representative Western blot (WB) (from n = 3 experiments) shows endogenous tuberin (~200 kDa) using anti-tuberin antibody and cTuberin-Myc (predicted 85 kDa) using anti-tuberin and anti-Myc antibodies. -Actin served as a loading control. (B) HEK293T cells were transfected with AAV-null and AAV-cTub-Myc plasmids and immunostained 72 hours later for tuberin (red) and c-Myc (green) with nuclear DAPI (blue). Scale bar, 100 m. The bar graph (bottom right) summarizes the cell count analysis (43 2% of the AAV-cTuberin-Myctransfected cells expressed c-Myc). (C) Cell death was quantified 72 hours after transfection using the Cytotoxicity LDH Assay Kit. Each bar represents the mean SD. (n = 3). ****P < 0.0001, compared with the positive apoptotic control (Bortezomib, 100 nM). (D) To further quantify transfection efficiency, HEK293T cells were transfected with AAV-CBA-cTub-Myc plasmid for 72 hours (n = 3 experiments) followed by sorting for the c-Mycpositive cells using flow cytometry. There was a significant increase in c-Mycpositive cells (50 1%) in the transfected cells (P < 0.0001) as compared to the nontransfected cells (4 1%). ****P < 0.0001.

COS-7 cells were cotransfected with plasmids for empty AAV (AAV-null), Myc-tagged full-length tuberin (Myc-FL-tuberin), AAV-CBA-cTuberin-Myc, Myc-tagged glycogen synthase kinase-3 (Myc-GSK-3), FLAG-tagged hamartin, and/or hemagglutinin (HA)tagged glutathione S-transferase (GST)tagged Rheb1 (HA-GST-Rheb1). Coimmunoprecipitation experiments performed with anti-Myc antibody showed that Myc-tagged cTuberin bound to FLAG-tagged hamartin and HA-tagged GST-Rheb1 to the same extent as Myc-FL-tuberin (Fig. 3). Myc-tagged GSK-3, used as a negative control, did not bind to FLAG-tagged hamartin or HA-tagged GST-Rheb1. These results indicated that cTuberin binds to hamartin and Rheb1 in cells, supporting a similarity in these biochemical parameters between cTuberin and full-length tuberin.

Representative blot (n = 3 experiments) after cotransfection of the Myc-tagged cTuberin (AAV-CBA-cTub-Myc) or full-length tuberin (Myc-FL-tuberin) along with FLAG-tagged hamartin and HA-tagged GST-Rheb1. Coimmunoprecipitation (co-IP) using anti-Myc antibody demonstrated that cTuberin-Myc interacts with both Flag-hamartin and HA-Rheb1 similar to Myc-FL-tuberin. Conversely, negative control Myc-GSK-3 showed no interaction with FLAG-hamartin or HA-GST-Rheb1.

For functional assessment tuberin and cTuberin on mTORC1 activity in vitro, we evaluated S6K T389 phosphorylation in cells expressing these proteins, together with hamartin and S6K, as described (24, 25). To determine whether cTuberin overexpression could inhibit mTORC1 activation, the Myc-tagged cTuberin plasmid was cotransfected with Flag-tagged hamartin and HA-tagged p70S6K (HA-S6K) reporter plasmids into HEK293T cells. As a control, a plasmid encoding Flag-tagged full-length tuberin was cotransfected with Flag-hamartin and HA-S6K plasmids. Hamartin and full-length tuberin coexpression inhibited phosphorylation of S6K T389, as expected, and similarly, coexpression of hamartin and cTuberin also decreased pS6K T389 levels (Fig. 4A), supporting the ability of cTuberin to bind to hamartin and efficaciously inhibit TORC1 activity. Level of pS6K T389 inhibition was quantified relative to HA-S6K using Fiji/ImageJ. Flag-hamartin cotransfected with AAV-GFP served as a control (normalized to 1.0), and cotransfection with full-length tuberin and cTub-Myc revealed a significant inhibition of S6K T389 phosphorylation by 69 and 56%, respectively (*P < 0.05; n = 3 separate experiments).

(A) Full-length Flag-tagged tuberin (Flag-tuberin), Myc-tagged cTuberin (AAV-cTub-Myc), or AAV-GFP plasmids were cotransfected into HEK293T cells along with full-length Flag-tagged hamartin (Flag-hamartin) and HA-tagged p70S6K (HA-p70S6K), which is phosphorylated at T389 by mTORC1 (latter used as a reporter for mTORC1 activation). Representative blot (n = 3 experiments) demonstrated similar inhibition levels of phosphorylated p70S6K (pS6K T389) with either full-length tuberin or cTub-Myc cotransfected with full-length hamartin. (B) Quantitation of decrease in S6K T389 phosphorylation was performed relative to HA-S6K using Fiji/ImageJ. Flag-hamartin cotransfected with AAV-GFP served as a control (normalized to 1.0), and cotransfection with full-length tuberin or cTub-Myc revealed inhibition of 69 or 56%, respectively, representing the results from three experiments. *P < 0.05.

To evaluate preclinical efficacy of the AAV9-CBA-cTuberin-Myc vector (hereafter referred to as AAV9-cTuberin), Tsc2 homozygous floxed mice (referred to as Tsc2-floxed or Tsc2flox) were first injected ICV at P0 with an AAV1-CBA-Cre recombinase vector (1 1012 vg/kg) to inactivate Tsc2 in a subset of neurons, astrocytes, and other cells in the brain (16). At P21, these AAV1-Creinjected mice were injected IV (retro-orbitally) with AAV9-cTuberin vector (9 1011 vg/kg) or AAV9-null vector (1 1013 vg/kg) and were compared to control animals that did not receive any IV injection. Tsc2-floxed AAV1-Creinjected (P0) mice had a median survival of 58 days, as did similar mice injected IV at P21 with AA9-null vector (mean survival of 58 days), mice injected IV at P21 with AAV9-cTuberin vector had the median survival of 462 days (P < 0.0001) (Fig. 5A). We also tested the potential toxicity of this dose of AAV9-cTuberin alone by injecting six Tsc2-floxed mice IV at P21 (in the absence of AAV1-Cre induced loss of Tsc2 at P0). All six mice survived over 500 days without apparent toxicity (Fig. 5A).

(A) Tsc2-floxed mouse pups were injected ICV with an AAV1-Cre vector (1 1012 vg/kg) at P0 to induce tuberin loss in multiple cell types in the brain. At 21 days, mice were injected IV with either AAV9-cTuberin (9 1011 vg/kg; n = 12) or AAV9-null (1 1013 vg/kg; n = 6) or noninjected (n = 6). Median survival of the AAV-cTuberin-injected mice (462 days, red line) was significantly longer than the non-cTuberin-injected mice (58 days, black line) (****P < 0.0001). Mice injected secondarily with the AAV9-null vector also died on average by 58 days (gray). Pups injected only with AAV9-cTuberin (no AAV1-Cre) all lived over 500 days. For (B) and (C), AAV1-Cre ICV (1 1010 vg/kg) was injected at P1 only or followed with AAV9-cTuberin (8 1012 vg/kg) IV at P21. (B) Body weights of Tsc2-floxed mice injected with AAV1-Cre vector, with and without AAV9-cTuberin vector, or noninjected were similar from P21 to P50. (C) For the rotarod test, the motor function of the Tsc2-floxed AAV1-Creinjected mice rescued by AAV9-CBA-cTuberin vectors was significantly better than that of the AAV1-Cre group and noninjected group. **P < 0.005. ns, not significant.

Different cohorts of mice were subjected to body weight measurement and motor function assessment starting at P21/22 for nave, noninjected animals, AAV1-Cre ICV injected (1 1010 vg/kg) at P1 only or followed with AAV9-cTuberin injected (8 1012 vg/kg) IV at P21. Body weights of these mice from age 21 to 50 days did not differ according to treatment (Fig. 5B). Movement was assessed using an automated rotarod apparatus with accelerating rotary velocity (4 going to 64 rpm over 2 min) to assess motor skills of the mice as time of latency to fall. A significant increase in latency was observed for the AAV1-Cre + AAV9-cTuberin as compared to the AAV1-Creinjected mice and naive mice (Fig. 5C). During animal handling, two mice of six Tsc2-floxed AAV-Creinjected mice (day 41) and two mice of seven Tsc2-floxed AAV-Creinjected + AAV-cTuberininjected mice (one each on days 47 and 50) manifested straub (vertical tail), humped back, and/or motor seizures, which did not, however, compromise their consequent rotarod performances (fig. S2).

Two other approaches were less effective at extending survival of AAV1-Cre ICVinjected Tsc2-floxed mice. In one, using a similar time scheme (fig. S3), Tsc2-floxed pups were injected with 1 1014 vg/kg AAV1-Cre ICV at P3 and then 3 1012 vg/kg of AAV1-cTuberin (in contrast to AAV9 serotype) IV at P21, with the higher amount of AAV1-Cre (without cTuberin) leading to death with a mean of 36 days and survival only being extended by AAV1-cTuberin to a mean of 54 days. This probably reflects the fact that AAV1 is less efficient at crossing the blood-brain barrier (BBB) than AAV9. In another experiment, the Tsc2-floxed pups were injected ICV with AAV1-Cre (1 1012 vg/kg) at P0, followed by ICV injection (in contrast to systemic injection) of 4.5 1013 vg/kg of AAV9-cTuberin at P3. This approach led to median survival of 50 days in Tsc2-floxed mice without cTuberin injection, while those injected with AAV9-cTuberin had extended median survival only up to 95 days (fig. S4). This experiment raises the possibility that other lesions in the body (in addition to the brain) resulting from ICV injection of AAV1-Cre were associated with death and were not sufficiently alleviated by ICV injection of the cTuberin vector and/or that the high dose AAV-cTuberin injected ICV into P3 pups had some toxicity (26).

In nave (normal) Tsc2-floxed mice, the ventricle is lined by a single layer of ependymal cells (Fig. 6A). Neuropathological examination at P42 revealed that ICV injection of AAV1-Cre in Tsc2-floxed mice at P0 led to multiple layers of ependymal and subependymal cells lining the lateral ventricle (indicating increased proliferation of these cells) (Fig. 6B, asterisk), which sometimes appeared as nodules along the ventricular lining (Fig. 6C). When these AAV1-Creinjected mice were treated with AAV9-cTuberin (IV injected at P21), there was apparent regression of ependymal/subependymal overgrowths (Fig. 6D). We also stained these mouse brain sections (P42) for Ki67 as an indication of cell proliferation. As expected, there was little-to-no proliferation of ependymal/subependymal cells lining the ventricles in the nave brain (Fig. 7A). In contrast, after AAV1-Cre injection at P0, there was marked proliferation of these cells, including apparent migration of dividing cells into the brain parenchyma (Fig. 7B), also seen after subsequent IV injection with AAV9-null vector (Fig. 7C). In contrast, IV injection of the AAV9-cTuberin vector decreased proliferation and inward migration of Ki67+ ependymal/subependymal cells (Fig. 7D).

Tsc2-floxed mouse pups were either not injected (nave) or injected ICV in both ventricles (1 1012 vg/kg) with an AAV1-Cre vector at P0. At 21 days, some mice were injected IV with AAV9-cTuberin (9 1011 vg/kg) or noninjected. At 42 days, all mice were euthanized. (A) Nave, noninjected brain (black arrowhead indicating the choroid plexus). (B and C) Tsc2-floxed mice with AAV1-Cre at P0 and no further injection showed (B) proliferation of ependymal/subependymal cells (asterisk) and (C) subependymal nodules. (D) Little-to-no subependymal overgrowth was detected in mice receiving both the P0 AAV1-Cre ICV injection and P21 IV AAV9-cTuberin injection. Representative images are shown. Magnification bar, 100 m. CC, corpus callosum; LV, lateral ventricle.

Tsc2-floxed mouse pups were either not injected (nave) or injected ICV in both ventricles (1 1012 vg/kg) with an AAV1-Cre vector at P0. At 21 days, some mice were injected IV with AAV9-cTuberin (9 1011 vg/kg), AAV9-null (1 1013 vg/kg) or noninjected. At 42 days, all mice were euthanized. (A) Nave, noninjected brain reveals little-to-no staining in the ependymal/subependymal layers. (B) Tsc2-floxed mice injected with AAV1-Cre vector only showed abnormal mitotic activity and apparent migration of cells (yellow arrows) away from the ventricular zone, as well as multiple ependymal/subependymal layers (green arrowheads) as compared to the nave group. (C) Tsc2-floxed mice injected with AAV1-Cre vector followed by AAV9-null vector showed abnormal mitotic activity of the cells and thickening of the subventricular zone. (D) The Tsc2-floxed mice injected with AAV1-Cre and then rescued with the AAV9-cTuberin vector showed a trend toward normalization of the ependymal/subependymal layer. The corresponding brain sections were counterstained with DAPI. The yellow asterisk denotes autofluorescence in the choroid plexus. Representative images are shown. Magnification bar, 100 m.

The brain sections (P42) were also immunostained for phosphorylated ribosomal protein S6 (pS6). We observed low pS6 expression in the whole brain sections of the noninjected (nave) mouse brain (Fig. 8A, top). In contrast, in AAV1-Cre ICVinjected Tsc2-floxed mice, pS6 expression was intense in many brain cells [Fig. 8, A (middle) and Bi], with the pS6-positive cells being significantly larger in size (Fig. 8Bii) and with a higher pS6 immunofluorescence signal (Fig. 8Biii). When the AAV1-Creinjected mice were subjected to IV injection of the AAV9-cTuberin vector at P21, the pS6 immunoreactive cells were significantly decreased in average size by 23% [P < 0.05; Fig. 8, A (bottom) and Bii] and showed a reduced pS6 signal by 28% (P < 0.05; Fig. 8Biii) consistent with reduced mTOR activity.

Tsc2-floxed mouse pups were either not injected (nave) or injected ICV (1 1012 vg/kg) with an AAV1-Cre vector at P0. At P21, some mice were injected IV with AAV9-cTuberin (9 1011 vg/kg) or noninjected. All were euthanized at P42. (A) Whole mouse brain sections from nave, AAV1-Cre, and AAV1-Cre+ AAV9-cTuberin injected mice stained for pS6 and DAPI. Representative whole brain sections (scale bar, 1 mm; eight-bitthresholded inverted images) indicated absence of pS6 puncta in nave group. In other groups, pS6 puncta appeared as darkened spots within the cerebral cortex and caudate putamen; high magnification inset images (scale bar, 100 m; 12-bitthresholded inverted images). (B) pS6 analysis included puncta density (i), size (ii), and intensity (iii). *P < 0.05; n = 3. a.u., arbitrary units. (C) Compared to nave pups, immunoblotting demonstrated AAV1-Cremediated decrease of tuberin (54%) and increase in pS6 (76%) in Tsc2-floxed mice injected with AAV1-Cre, relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) with nave brain as control (normalized to 1.0; *P < 0.05; n = 3). (Di) Ct values for biodistribution of AAV vector genomes in the brain and liver measured by qPCR. (Dii) Ct value of GAPDH and cTuberin cDNAs in brains of nave animals injected with AAV1-Cre only or with AAV1-Cre and AAV9-cTuberin. n.d., not determined.

To assess the Cre-mediated loss of tuberin and activation of mTOR activity in vivo, newborn pups (P0, n = 3) were injected ICV with AAV1-CBA-Cre recombinase vector (AAV1-Cre at dosage of 1 1012 vg/kg), and another three noninjected (nave) pups were included as controls. One week after injection of vector, brain protein lysates were collected for immunoblotting with anti-tuberin and anti-pS6 antibodies. There was significant reduction in expression of tuberin by 54% (P < 0.05) and significant increase of pS6 by 76% (P < 0.05) in animals injected with AAV1-Cre, confirming that the Cre recombinase mediates loss of tuberin and activation of mTOR in the treated mice (Fig. 8C).

To examine the vector biodistribution in the injected animals, Tsc2-floxed animals were injected ICV at P0, with an AAV1-CBA-Cre recombinase vector (AAV1-Cre; 1 1012 vg/kg, n = 4). At P21, these AAV1-Creinjected mice were injected IV with AAV9-cTuberin vector (9 1011 vg/kg). One week after injection, DNA was extracted from the brain and liver of these animals. For comparison, another three Tsc2-floxed animals subjected to no injections were used as controls. For quantitative polymerase chain reaction (qPCR) analysis of AAV genomes (probes and primer specific), 50 ng of DNA was used as a template, and primers and probes were designed to amplify the cTuberin in the infected animal (fig. S5). cTuberin DNA was not detected in the noninjected control group (Fig. 8D). Cycle threshold (Ct) values for the Tsc2-floxed animals injected with AAV1-Cre and AAV9-cTuberin vectors were readily detectable with approximately 30.8 2.6 and 17.2 0.2 cycles for brain and liver tissue, respectively (Fig. 8Di). The large difference between the AAV genomes in brain compared to liver is likely due to both the high tropism of systemically injected AAV for the liver and the relatively low dose of vector injected (9 1011 vg/kg). To detect cTuberin transgene expression, total RNA was extracted from the brains and livers of another set of animals, including noninjected controls; Tsc2-floxed animals injected with AAV1-Cre only, and Tsc2-floxed animals injected with AAV1-Cre and AAV9-cTuberin vectors (n = 3 for all groups), with the dosage of AAV1-Cre ICV injected at P1 (1 1010 vg/kg) or combined with AAV9-cTuberin injected IV at P21 (1.8 1012 vg/kg). Quantitative reverse transcription PCR (RT-qPCR) analysis indicated that cTuberin mRNA was undetectable in the noninjected control group and those injected with AAV1-Cre only. In contrast, in both brains and livers, we detected cTuberin mRNA in mice injected with AAV9-cTuberin at levels of Ct 36.8 3 and 34.8 0.5 cycles, respectively (Fig. 8Dii). We did not detect cTuberin cDNA when reverse transcriptase was omitted from the RT reaction, indicating that we were detecting bona fide cTuberin mRNA and not sample contamination with AAV-cTuberin genomes.

This is the first description of an alternative mode of therapy for TSC type 2 (TSC2) involving gene replacement using an AAV vector encoding a condensed form of tuberin, termed cTuberin. We developed a stochastic mouse model for central nervous system (CNS) lesions in TSC2 in which homozygous Tsc2-floxed mice (15, 27) are injected ICV in the newborn period (P0 to P3) with an AAV1 vector expressing Cre recombinase, as described for our stochastic TSC1 model (14). AAV1-Cre injection in the Tsc2-floxed model resulted in death at about 58 days. Death appeared to be due primarily to hydrocephalus caused by ependymal/subependymal overgrowths blocking cerebrospinal fluid flow, with whole-body pathology revealing no overt lesions except in the CNS. Although signs of seizures were noted in a few mice during motor performance assessment, these animals recovered normal activity. Experiments showed that IV injection of AAV9-cTuberin vector into this stochastic Tsc2-floxed mouse model on day 21 extended life span in most mice (9 of 12) to at least 450 days. Histochemical/immunohistochemical analysis of the brains supported a resulting reduction in size of ependymal/subependymal lesions, decreased proliferation of cells in the subependymal zone, and reduced phosphorylation of S6 kinase driven by mTOR activity. This study offers a potential single treatment paradigm for improving the outcome of patients with TSC2.

Limitations to this stochastic Tsc2 mouse model include the fact that floxed alleles (before Cre exposure) are normal in function during prenatal development and that Cre recombinase usually knocks out both alleles in a cell at once, which is different from the case in TSC2 patients, most of whom are heterozygous for one mutant and one normal allele in most-to-all cells in their body. TSC2 heterozygosity itself may compromise some cell functions and contribute to aspects of the disease phenotype (1, 28, 29). Further, the model used here is CNS oriented, with most pathology in the brain; whereas in TSC patients, a number of organs in addition to the brain are affected. In addition, this Tsc2 mouse model does not show all the brain abnormalities observed in human TSC2, many of which form prenatally, such as cortical tubers, disorganized cortical lamination, dysplastic neurons, and giant cells (30). Strengths of this model are that there is loss of tuberin expression in a number of different cell types in the brain with variation for animal to animal, as occurs in patients with TSC. This is in contrast to commonly used models where Tsc2-floxed mice are mated to mice expressing Cre recombinase under a cell-specific promoter, e.g., the synapsin promoter, in which case most and only neurons lose expression at embryonic day 12.5 (31).

The central portion of tuberin that was removed to fit coding sequences into the AAV vector contains a number of phosphorylation sites that are involved in regulating mTOR activity under some circumstances, with three of these sites bearing missense mutations associated with TSC2, suggesting that they may contribute to the disease phenotype or create truncated, nonfunctional proteins (6). By comparison, there is an ortholog of human tuberin in Schizosaccharomyces pombe that lacks about 500 amino acids in the equivalent central region of human tuberin, suggesting that these sites are dispensable to some functions (32). Further, some of the key Akt phosphorylation sites in mammalian tuberin are not essential in Drosophila (33), and phosphorylation sites for Akt, ribosomal protein S6 kinase, and AMP-activated protein kinase (AMPK) in the central region of human tuberin are not present in Schizosaccharomyces or Dictyostelium (34), suggesting that these sites may not be critical for function. Given the critical role of phosphorylation sites in tuberin in growth factor and cytokine signaling in mammalian cells, one would anticipate that cTuberin in TSC2-null cells would lack some of these regulatory controls. However, in the Eker rat model of TSC2, which is prone to renal carcinomas, the C-terminal region alone (amino acids 1425 to 1755) of rat tuberin suppresses tumor formation in a dose-dependent manner (35). Fortunately, in TSC2 patients, only a very small fraction of cells in the body suffer loss of tuberin, and most damage is done by the enlargement and proliferation of these deficient cells. Thus, if overgrowths can be suppressed by cTuberin, then that would bring therapeutic benefit for many of the symptoms of the disease, although the cells would not be fully normalized. So far, in cultured cells, cTuberin has been shown to bind to hamartin, and overexpression of cTuberin was not found to be toxic. cTuberin inhibited mTORC1 signaling in these cells to the same extent as tuberin, supporting the use of cTuberin as an effective replacement for tuberin for some cell properties.

Subependymal nodules (SENs) occur in 10 to 15% of children with TSC, usually appearing after birth and being more severe in TSC2 than TSC1 (3638). SENs can enlarge into subependymal giant cell astrocytomas (SEGAs) during the first decade of life causing obstruction of cerebrospinal fluid flow, potentially leading to life-threatening hydrocephalus, as well as endocrinopathy and visual impairment (36, 37, 39, 40). Under optimal care, infants and children with TSC are monitored for subependymal lesions by magnetic resonance imaging (MRI) every 6 to 12 months. The two current standards of care are neurosurgical removal of SEGAs through craniotomy, which can be associated with significant morbidity (37), or treatment with rapalogs, which inhibit mTOR activity. Rapalogs have proven effective in reducing lesion size, but they require continuous treatment and have limited access to the brain after peripheral administration. Potential problems with this class of drugs include a compromise of immune function (41), interference with white matter integrity (42), and possible interference with brain development in early childhood (43). In several studies, the mTOR pathway has been found to be critical to neurodevelopment, including neuronal growth, axonal guidance, synapse formation, and myelination (4446). Inhibition of mTOR by rapalogs may contribute to the observed memory dysfunction following prenatal/postnatal drug treatment in Tsc mouse models (47) and the behavioral abnormalities in wild-type mice treated prenatally with rapamycin (48). Some physicians do not recommend the use of these drugs in children or pregnant women as long-term effects on growth and development in pediatric patients are not fully known (43). Although in at least one study, rapalog treatment was reported to have no significant effect on neurocognitive function or behavior in children with TSC (49).

Our premise is that current therapies for children with TSC may have associated morbidity resulting in the potential for decreased mental functions. Another therapeutic approach would be intravascular administration of an AAV vector that can cross the BBB encoding a replacement gene for the mutant TSC1 or TSC2 alleles. Since SENs are slow growing, there would be time to monitor their size by MRI over several months and leave open the opportunity to administer standard-of-care treatment, as needed. It is hoped that gene replacement therapy might reduce use of more problematic standard-of-care procedures in young children and provide long-lasting benefit with a single administration. Certain serotypes of AAV, such as AAV9, are able to penetrate the BBB as well as deliver to peripheral tissues (13). Thus, with IV delivery, extra copies of the replacement gene would be provided to multiple tissues, including brain, kidney, liver, and lungs, which might reduce the likelihood that somatic mutations in TSC genes later in life would lead to disruptive hamartomas.

Advantages of AAV gene therapy are the potential for a single vector injection yielding long-term transgene expression in nondividing cells. It is assumed that once a tuberin analog is delivered to cells in TSC2 lesions, they would shrink and stop dividing and, hence, retain transgene expression. Gene therapy may be a viable option for infants/children with TSC to reduce potential compromise of brain functions caused by congenital lesions and secondary sequelae of these lesions. AAV9 vectors have been used in young mice with spinal muscular atrophy (SMA) for gene replacement of the survival motor neuron (SMN) protein using both IV (50) and intrathecal (51) gene delivery. An AAV9-SMN drug, Zolgensma (Novartis), is now U.S. Food and Drug Administrationapproved for IV treatment of babies/children with SMA. Two critical aspects of successful gene therapy with AAV vectors are as follows: (i) a known target, in the case of TSC2 loss of function of tuberin; and (ii) no toxicity resulting from overexpression of the replacement protein, since levels of expression cannot at present be regulated. There is a predicted reduced chance of toxicity of cTuberin as it should only be active in a 1:1 complex with hamartin, and hamartin levels are normal in TSC2 null cells (52), with cTuberin not bound to hamartin presumably being degraded. So far, no toxic effects of cTuberin expression have been observed in cells in culture or in mice. Clinical trials should be facilitated by the ability to image reduced lesion size within months by MRI due to shrinking of cell volume and inhibition of cell proliferation, as was found in the rapalog trial for renal angiomyolipomas (53). Typically, AAV vectors are just administered once due to previous exposure to the AAV virus in life eliciting an immune response to the capsid and reducing secondary transduction (54). If replacement is insufficient to reduce symptoms or new TSC2 null lesions arise later in life after AAV gene replacement, it would still be possible to treat patients with rapalogs or possibly exoAAV (55). These studies support the potential of AAV gene therapy for TSC2, which might be especially useful in infants and children where drug inhibition of the mTOR pathway may interfere with early brain development.

The AAV vector plasmid, AAV-CBA-Cre-BGHpA, was derived as described in Prabhakar et al. (16). These AAV vectors carry AAV2 inverted terminal repeat elements, and gene expression is controlled by a hybrid promoter (CBA) composed of the cytomegalovirus (CMV) immediate/early gene enhancer fused to the -actin promoter (23). To increase the efficiency of cTuberin translation (for future use in human gene therapy approach), cDNA encoding cTuberin was human codon-optimized before gene synthesis by GenScript Biotech (Piscataway, NJ, USA). AAV vector plasmid, AAV-CBA-cTuberin-c-Myc, was derived from the plasmid pAAV-CBA-W (56). This vector contains the CBA promoter driving cTuberin, followed by a WPRE and both SV40 and bovine growth hormone (BGH) polyadenylation (poly A) signal sequences. Our cTuberin construct contains the following: ACC (Kozak sequence) :: amino acids 1 to 450 of human tuberin::gly/ser linker :: amino acids 1515 to 1807 of human tuberin :: c-Myc tag = 2307 bp encoding an 85-kD protein (fig. S1). The pAAV-CBA-W, which contains the CBA promoter, WPRE, and poly A sequences, but no transgene, served as AAV-null in our studies.

AAV1 and AAV9 serotype vectors were produced by transient cotransfection of HEK293T cells by calcium phosphate precipitation method of vector plasmids (e.g., AAV-CBA-cTuberin-Myc), adenoviral helper plasmid pAdF6, and a plasmid encoding AAV9 (pAR9) or AAV1 (pXR1) rep and capsid genes, as previously described (57). All AAV vectors carried the identity of all PCR-amplified sequences as confirmed by sequencing. Briefly, AAV vectors were purified by iodixanol density gradient centrifugation. The virus-containing fractions were concentrated using Amicon Ultra 100-kDa molecular weight cut-offs (MWCO) centrifugal devices (EMD Millipore, Billerica, MA, USA), and the titer vector genomes (vg) per milliliter was determined by quantitative real-time PCR amplification with primers and TaqMan probe specific for the BGH poly A signal.

HEK293T cells [American Type Culture Collection (ATCC)] and COS-7 cells (ATCC, Manassas, VA, USA) were cultured in Dulbeccos modified Eagles medium (DMEM; Thermo Fisher Scientific, Hampton, NH, USA) supplemented with 10% fetal bovine serum (FBS; Gemini Bio Products, West Sacramento, CA, USA) and 1% penicillin/streptomycin (Thermo Fisher Scientific). The cell cultures were periodically screened to ensure they are free from mycoplasma contamination using the PCR Mycoplasma Detection Kit (ABM, G238, Richmond, BC, Canada).

HEK293T cells were seeded in 96-well plates (10,000 cells per well) and, after 24 hours, transfected with various plasmid DNAs (AAV-null, AAV-GFP, and AAV-cTuberin) at 250 ng/10,000 cells using Lipofectamine 2000, according to the manufacturers instructions (Life Technologies, Carlsbad, CA, USA) in Opti-MEM (Life Technologies). Six hours later, transfection media was removed and replaced with DMEM (10% FBS and 1% Penicillin-Streptomycin solution), and cells were allowed to grow for 72 hours. One group of cells was treated with potent proteasome inhibitor Bortezomib (VELCADE; Millennium Pharmaceuticals Inc., Cambridge, MA, USA) (58) at 250 nM for 72 hours, as a positive control for toxicity. Cellular toxicity caused by plasmid DNA transfection was assessed by quantification of extracellular LDH activity using LDH assay kit-WST (Dojindo Molecular Technologies Inc.), following the manufacturers instructions. Briefly, the supernatant for each transfected or treated sample was collected and incubated with substrate for 30 min at 37C. Following incubation, stop solution was added, and absorbance was measured at 490 nm.

Briefly, cultured cells were harvested in lysis buffer [50 mM Hepes (pH 8.0), 150 mM NaCl, 2 mM EDTA, 2.5% sodium dodecyl sulfate, 2% CHAPS, 2.5 mM sucrose, 10% glycerol, 10 mM sodium fluoride, 2 mM sodium vanadate, 1 mM phenylmethylsulfonyl fluoride (Sigma-Aldrich, St. Louis, MO, USA), 10 mM sodium pyrophosphate, and protease inhibitor cocktail (P8340, Sigma-Aldrich)]. After sonication and incubation at 8C for 10 min, the samples were centrifuged at 14,000g for 30 min at 8C. Equal amounts of protein, determined by a detergent-compatible protein assay kit (Bio-Rad Laboratories, Hercules, CA, USA), were boiled for 5 min in Laemmli sample buffer (Bio-Rad), separated by SDSpolyacrylamide gel electrophoresis (PAGE), and transferred onto nitrocellulose membranes (Bio-Rad). Equal protein loading was confirmed by Ponceau S staining. The membranes were blocked in 2% blocking reagent (GE Healthcare, Pittsburgh, PA, USA) for 1 hour at room temperature (RT) and incubated with primary antibodies overnight at 4C. Anti-tuberin/TSC2 (#3612), antiphospho-S6 (#2211), anti-S6 (#2212), anti-Myc (clone 9B11, #2276) (Cell Signaling Technology, Danvers, MA, USA), anti-actin (#A5441), anti-FLAG (clone M2, #F1804) (Sigma-Aldrich), anti-HA (clone F-7, sc-7392, Santa Cruz Biotechnology, Dallas, TX, USA), and antiglyceraldehyde-3-phosphate dehydrogenase (GAPDH) (#CB1001, EMD Millipore) were used as primary antibodies. Anti-rabbit or anti-mouse immunoglobulin G antibody conjugated with horseradish peroxidase was used as a secondary antibody (Thermo Fisher Scientific). Enhanced chemiluminescence reagent, Lumigen ECL Ultra (TMA-6) (Lumigen, Southfield, MI, USA), was used to detect the antigen-antibody complexes.

For immunoprecipitations, COS-7 cells were transfected with plasmid vectorsAAV empty, AAV-CBA-cTuberin-Myc, pcDNA-hamartin-FLAG (V. Ramesh laboratory), pReceiver-M09/tuberin-Myc (catalog no. EX-Z5884-M09, GeneCopoeia, Rockville, MD, USA), pCMV-Tag3A-Myc-GSK-3 (GSK-3 sequence was cloned into pCMV-Tag3A vector; catalog no. 211173-51, Agilent Technologies, Santa Clara, CA, USA), and pRK5-HA-GST-Rheb1 [catalog no. 19310, Addgene, Watertown, MA, USA; provided by Sancak et al. (59)] using Lipofectamine 2000 (Life Technologies). Cells were lysed with ice-cold phosphate-buffered saline (PBS) (pH 7.4) containing 1% Triton X-100, 2 mM EDTA, 10 mM sodium pyrophosphate, 1 mM phenylmethylsulfonyl fluoride, 2 mM sodium vanadate, 10 mM sodium fluoride, and proteinase inhibitors cocktail (Sigma-Aldrich). Lysates were centrifuged at 15,000 rpm for 10 min at 4C, and protein concentration was measured using the Bradford protein assay (Bio-Rad). One milligram of lysates was incubated with 2 g of anti-Myc-tag antibody (catalog no. 16286-1-AP, Proteintech, Rosemont, IL, USA) in the presence of Protein A/G Agarose (Santa Cruz Biotechnology) at 4C overnight. After washing twice with ice-cold modified PBS buffer (pH 7.4) (287 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 1.8 mM KH2PO4, 0.05% Triton X-100, and 1 mM EDTA), resins were incubated in 30 l of 0.2 M glycine-HCl buffer (pH 2.5) (Polysciences Inc. Warrington, PA, USA) at RT for 15 min, and then the supernatants were collected and neutralized by adding an equal amount of 1 M tris-HCl (pH 8.0) (Sigma-Aldrich). To increase stringency during the washing, NaCl concentration was increased from 137 to 287 mM in the modified PBS buffer to reduce ionic protein interaction. Eluted immunoprecipitates or whole-cell lysates were separated by SDS-PAGE and analyzed by immunoblotting with antibodies specific for Myc-tag (dilution 1:5000) (catalog no. 2276, Cell Signaling Technology), FLAG-tag (1:25,000) (catalog no. F1804, Sigma-Aldrich), and HA-tag (1:3000) (catalog no. sc-7392, Santa Cruz Biotechnology). Anti-mouse antibody conjugated with horseradish peroxidase (Thermo Fisher Scientific) was used as a secondary antibody (dilution 1:25,000). Enhanced chemiluminescence reagent, Lumigen ECL Ultra (TMA-6) (Lumigen, Southfield, MI, USA), was used to detect the antigen-antibody complexes.

To assess the functional activity of AAV-cTuberin-Myc, we cotransfected HEK293T cells, as previously described with minor modifications (60). Plasmids included HA-tagged p70S6 kinase (HA-p70S6K) (60), which is phosphorylated (pS6K T389) by mTORC1 and was used as a reporter for mTORC1 activation, and Flag-tagged hamartin (Flag-hamartin) (60), along with AAV-cTuberin-Myc. Full-length Flag-tagged tuberin (Flag-tuberin) (60) was used as a positive control, and AAV-GFP was used as a negative control. Transfections were carried out for 48 hours using Lipofectamine 2000. Cell lysates were prepared using radioimmunoprecipitation assay lysis buffer, and immunoblotting was performed, as described (60). Briefly, proteins were separated on a Novex 4 to 12% tris-glycine gradient gel (Life Technologies) followed by transfer to 0.45 M nitrocellulose membrane (Bio-Rad). Antibodies included M2 anti-Flag mouse monoclonal (Sigma-Aldrich), anti-hamartin and anti-pS6K (T389) (Cell Signaling Technology), anti-Myc mouse monoclonal (9E10, University of Iowa Hybridoma Bank), and anti-HA mouse monoclonal (HA.11, BioLegend/Covance, San Diego, CA, USA).

HEK293T cells were seeded in a six-well plate (500,000 cells per well) for 24 hours. The cells were then transfected with plasmid DNAs (AAV-null, AAV-GFP, and AAV-cTuberin) at 2.5 g/500,000 cells using Lipofectamine 2000 in Opti-MEM. Six hours later, transfection media was removed and replaced with DMEM (10% FBS and 1% PS), and cells were grown for 72 hours. Cells were washed twice in PBS, and proteins were extracted with protein extraction solution (PRO-PREP, iNtRON Biotechnology, Korea) for 20 min at 20C. The cell lysates were centrifuged at 14,000g at 4C. Protein concentrations of cell lysates were determined using a Bio-Rad protein assay kit. Equal amounts of protein (20 g) were separated using 4 to 12% precast NuPAGE bis-tris SDS-PAGE gels (Invitrogen) and transferred onto nitrocellulose membranes (Thermo Fisher Scientific Inc., Rockford, IL, USA). Membranes were blocked for 1 hour in tris-buffered saline (TBS) with 0.1% Tween 20 and 5% nonfat dry milk, followed by an overnight incubation with primary antibody to tuberin (#3990, 1:1000 dilution, Cell Signaling Technology diluted in the same buffer at 4C). On the next day, the membranes were washed with TBS with 0.1% Tween 20 (three times, 5 min each) followed by incubation with the appropriate horseradish peroxidaseconjugated secondary antibodies (Jackson ImmunoResearch Laboratories, West Grove, PA, USA) for 1 hour at RT. An enhanced chemiluminescence kit (Pierce ECL Western Blotting Substrate, Thermo Fisher Scientific, Waltham, MA, USA) was used to detect protein expression. The optical density of each band was determined on Western blots scanned with a G:Box (Syngene, Cambridge, UK).

Brains and livers were flash-frozen to determine AAV genome biodistribution and expression of transgene mRNA. Genomic and AAV vector DNA was isolated using the Qiagen DNeasy Blood and Tissue Kit (catalog no. 69504) according to the manufacturers instruction. Total RNA was extracted using the Qiagen RNeasy Lipid Tissue Mini Kit (catalog no.74804) and Qiagen RNeasy Mini Kit (catalog no. 74104), with additional on-column deoxyribonuclease (DNase) digestion with the Qiagen RNase-free DNase set (catalog no. 79254) to ensure digestion of AAV-cTuberin genomes. Then, extracted RNA was converted to cDNA using the SuperScript VILO cDNA Synthesis Master Mix (Thermo Fisher Scientific, catalog no. 11754-050), according to the manufacturers protocol. A no-RT set of samples for the AAV-cTuberin group was included to confirm detection of cDNA derived from cTuberin mRNA and not contaminating AAV-cTuberin genomes. Using 50-ng genomic DNA as template, TaqMan qPCR was performed using custom TaqMan probe and primers to 3 end of cTuberin and c-Myc tag of the transgene expression cassette (forward primer, 5-AGCCAACACCAGGATACGAA-3; reverse primer, 5-GCTAATCAGCTTCTGCTCCAC-3; probe, 5-FAM- AGCGGCTGATCTCCTCCGTGG-MGB-3) (fig. S5). For each sample, a separate qPCR was performed using TaqMan probe and primer sets (Thermo Fisher Scientific, assay ID Mm01180221_g1, gene symbol Gm12070) that detects GAPDH genomic DNA, to ensure equal genomic DNA input for each sample. For each organ/tissue, the AAV vector genome copies for each sample were adjusted by taking into account any differences in GAPDH Ct values using the following formula: (AAV vector genome copies)/(2Ct). The Ct value was calculated as GAPDH Ct value (sample of interest) average GAPDH Ct value (sample with highest Ct value). Data were expressed as AAV vector genomes per 50 ng of genomic DNA.

Experimental research protocols were approved by the Institutional Animal Care and Use Committee for the Massachusetts General Hospital (MGH) following the guidelines of the National Institutes of Health for the Care and Use of Laboratory Animals. Experiments were performed on Tsc2c/c-floxed mice [Tsc2-floxed; (61)]. These mice have a normal, healthy life span. In response to Cre recombinase, the Tsc2c/c alleles are converted to null alleles. For vector injections, in the neonatal period (P0 to P3), pups were cryo-anesthetized and injected with 1 to 2 l of viral vector AAV1-CBA-Cre into each cerebral lateral ventricle with a glass micropipette (70 to 100 mm in diameter at the tip) using a Narishige IM300 microinjector at a rate of 2.4 psi/s (Narshige International, East Meadow, NY, USA). Mice were then placed on a warming pad and returned to their mothers after regaining normal color and full activity typical of newborn mice. At 3 weeks of age (P21), mice were anesthetized with isoflurane (Baxter Healthcare, Deerfield, IL, USA) inhalation [3.5% isoflurane in an induction chamber and then maintained anesthetized with 2 to 3% isoflurane and oxygen (1 to 2 liters/min) for the duration of the injection]. AAV vectors were injected retro-orbitally into the vasculature in a volume of 60 l (AAV1 or AAV9) of AAV-cTuberin-Myc using a 0.3-ml insulin syringe over less than 2 min (62) or noninjected.

Eighteen measurements of the body weight of the animals were recorded from P23 to P50. To assess motor coordination, animals were placed on an automated rotarod apparatus (Harvard Apparatus, Holliston, MA, USA) using accelerated velocities (4 to 64 rpm over 120 s). Each animal was assessed three times with 5-min rest intervals in each session for nine sessions 3 to 4 days apart. For each assessment, the time ended when the mouse fell off the treadmill or when the time interval elapsed. All functional assessment tests were performed blinded with respect to the mouse genotype.

HEK293T cells were seeded on coverslip coated with poly-d-lysine (25,000 cells per coverslip) for 24 hours. The cells were then transfected with plasmid DNAs (AAV-null, AAV-GFP, and AAV-cTuberin) at 250 ng/25,000 cells using Lipofectamine 2000 in Opti-MEM. Six hours later, transfection media was removed and replaced with DMEM (10% FBS and 1% PS), and cells were grown for 72 hours. The cells were fixed with 4% paraformaldehyde (PFA) (Boston BioProducts, Ashland, MA, USA) for 10 min at RT followed by permeabilization using 0.01% Triton X-100 (Sigma-Aldrich) in PBS (PBST) for 10 min at RT. The cells were then blocked with 3% bovine serum albumin (BSA) in PBST for 1 hour at RT, followed by overnight incubation with primary antibodies at 4C [primary antibodies: c-Myc (1:400 dilution; 9E10, Life Technologies)] and GFP (1:400 dilution; A11122, Life Technologies). The cells were then washed three times for 5 min in PBST and incubated with secondary antibody (goat anti-mouse 488, Jackson ImmunoResearch Laboratories) (1:400 dilution), for 1 hour at RT. The cells were washed three times for 5 min using PBST, mounted with Vectashield containing DAPI (Vector Laboratories, Burlingame, CA, USA). Note that, unfortunately, we were not able to detect cMyc in brain sections using several sources of c-Myc antibodies.

The mouse brains were harvested and subjected for standard histological processing as described (14). Five-micrometer sections were stained with hematoxylin and eosin. For frozen sections, adult mice were euthanized using ketamine/xylazine (100:10) (Akorn Inc., Lake Forest, IL, USA) followed by transcardiac perfusion with 1 PBS and 4% PFA in PBS overnight at 4C, cryo-protected with 25% sucrose in PBS, and embedded in optimal cutting temperature medium (catalog no. 4583, Tissue Teck). Brain sections were prepared in 10-mm coronal sections and were blocked in 10% BSA in 1 PBS + 0.3% Triton X-100 for 1 hour at RT and subsequently incubated with rabbit anti-Ki67 (1:1000; #ab15580, Abcam) or rabbit anti-phospho-S6 ribosomal protein (Ser235/236) (1:400; #2211, Cell Signaling Technology) overnight at 4C. Following three washes in 0.1 PBS, the sections were incubated with secondary antibody Alexa 555 (1:400; Jackson ImmunoResearch Laboratories) for 1 hour at RT. The sections were then washed three times with 1 PBS and mounted with DAPI mounting medium (Vectashield, #H-1200).

Whole mouse brain sections immunostained for pS6 (biological triplicates for each group, three coronal sections per mouse) were imaged using a Nikon Ti2 inverted microscope equipped with W1 Yokogawa Spinning disk scanhead with 50-m pinholes, a Toptica 4 laser launch, and an Andor Zyla 4.2 Plus sCMOS monochrome camera. The slides were mounted on a Nikon linear encoded motorized stage, and the mouse whole brain sections were scanned using Plan Apo 20/0.8 differential interference contrast (DIC) I objective lens objective lens at 405 nm for DAPI (100-ms exposure) and 561 nm for pS6 staining (100-ms exposure). Signals were collected using a Semrock di01-t405/488/568/647 dichroic mirror and Chroma 455/50 or 605/52 nm emission filters. Images were captured using NIS AR 5.02 acquisition software and 12-bit gain four-camera setting. A series of images were captured and stitched together using blending algorithm with 15% overlap among images.

Stitched images were analyzed in Fiji, an open source image processing package based on ImageJ (63). All images were thresholded within the 80 to 800 tonal range for both DAPI and pS6 staining. An outline was manually drawn to delineate choroid plexuses, ventricles, large empty spots, and meninges from the whole mouse brain section image. These regions are known to contain significant amounts of autofluorescence and therefore were excluded from downstream analysis. Within the confined region of interests (ROIs), we measured the area for the whole brain section. To identify pS6 puncta size and intensity within them, the thresholded pS6 channel image was converted into eight-bit image and further thresholded within the 70 to 255 tonal range. Subsequently, particle analysis was performed to identify any puncta within 5 to 200 m2 and 0.1 to 1.0 circularity parameters. The area for each punctum was measured. These puncta ROIs were then used to identify raw integrated density on original unthresholded 12-bit brain section images. Normalized pS6 puncta number of a brain section was calculated by dividing the total number of pS6 puncta by the brain section area.

All analyses of survival curves (Mantel-Cox test and log-rank test) were performed using GraphPad Prism software (GraphPad Software Inc., La Jolla, CA, USA). Flow cytometry analysis on c-Mycpositive cells was analyzed using unpaired t test. Western blot analysis on pS6 and tuberin expression levels in the mouse brain and PS6 puncta parameters were analyzed using unpaired t test. LDH cytotoxicity assay and Western blot analysis on relative levels of S6K T389 phosphorylation were analyzed using one-way analysis of variance (ANOVA) test. P values of <0.05 were considered statistically significant.

Acknowledgments: We thank S. McDavitt for editorial assistance, M. F. Lee (Medical Photographer in Pathology Media Laboratory, MGH) for imaging training, M. Zinter (Vector Core, MGH, Charlestown, MA, USA) for AAV vector packaging, and M. Whalen for the use of the rotarod. Funding: This work was supported by DOD Army Grant W81XWH-13-1-0076 (to X.O.B.), NIH R01GM115552 (to M.K.), NIH NIDCD R01DC017117-01A1 (to C.A.M.), NIH NINDS 1R61NS108232 (to X.O.B., C.A.M., and V.R.), and NIH NS109540 (to V.R.). We would like to acknowledge the MGH Vector Core for the production of viral vectors (supported by NIH/NINDS P30NS045776; B.A.T.) and P. M. Llopis, Microscopy Resources on the North Quad (MicRoN), Harvard Medical School, NRB-Longwood, MA, USA. Author contributions: X.O.B., S.P., D.Y., C.A.M., and M.K. conceived and designed the experiments. S.P., P.-S.C., R.L.B., X.Z., and S.K. performed the experiments. S.P., P.-S.C., K.-H.L., and S.K. analyzed the data. S.P., P.-S.C., D.Y., B.A.T., E.A.T., X.Z., R.L.B., R.T.B., D.J.K., A.S.-R., B.G., K.-H.L., V.R., M.K., C.A.M., and X.O.B. wrote and edited the paper. Competing interests: X.O.B., S.P., D.Y., and C.A.M. have filed a provisional patent application for the cTuberin construct. C.A.M. has a financial interest in Chameleon Biosciences Inc., a company developing an enveloped AAV vector platform technology for repeated dosing of systemic gene therapy. X.O.B., V.R., and C.A.M.s interests are reviewed and managed by MGH and Partners HealthCare in accordance with their competing interest policies. All other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Plasmid requests can be provided by MGH pending scientific review and a completed material transfer agreement. Requests for the plasmid should be submitted to C.A.M. at cmaguire{at}mgh.harvard.edu.

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Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin - Science Advances

BEIJING, Jan. 8 (Xinhua) -- For the first time, a genome-wide CRISPR-based screening technology has identified a new driver of cellular senescence. It can form part of new strategies to delay aging and prevent aging-associated diseases, Chinese researchers said.

By screening and identifying more than 100 genes responsible for the aging of human cells, the research team demonstrated that knocking out, or disabling, some genes by CRISPR can discourage the aging of human mesenchymal precursor cells (hMPCs). Among the genes that lead to senility, and KAT7 (a histone acetyltransferase), is one of the catalysts for aging.

Knocking out KAT7 has been proven effective in alleviating cellular senescence in the team's experiments, said Zhang Weiqi, a researcher at the Beijing Institute of Genomics under the Chinese Academy of Sciences. The scientists managed to reduce the proportion of the senescent cells in the livers of aged mice and prolonged the lifespan of physiologically aged mice and those with progeria.

The novel gene therapy, based on disabling a single gene or using KAT7 inhibitors, could extend mammal life. It could also slow down the aging of human liver cells. It suggests a massive potential for its application in translational medicine against human aging.

The study was published on Thursday in Science Translational Medicine online.

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Chinese researchers discover new anti-aging gene therapy - The Star Online

Sana Biotechnology was founded in 2018 with a mission of solving some of the most difficult challenges in gene and cell therapy. Toward that end, the company is engineering hypoimmune stem cells that can evade detection and destruction by the immune system.

Now, some of Sanas founders, who are scientists at the University of California, San Francisco (UCSF), are describing how these engineered stem cells are able to shut down the immune systems natural killer (NK) cells. They believe their findings could enhance the development of implantable cell therapies, as well as cancer immunotherapies, they reported in the Journal of Experimental Medicine.

The ability to evade NK cells could enhance a range of experimental treatments, including implants of insulin-producing cells for patients with diabetes and cardiac cells to repair heart damage. These cells are typically rejected by the immune systema problem hypoimmune stem cells were designed to circumvent.

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The UCSF team used gene modification technology to design the cells so they avoid the immune responses that are either built into the bodys defense system or learned. The researchers achieved that feat by engineering the cells to express the protein CD47, which shuts down innate immune cells by activating signal regulatory protein alpha, or SIRP-alpha.

The researchers were surprised to discover that the hypoimmune stem cells were able to escape NK cells, even though NK cells were not previously known to express SIRP-alpha. Rather than studying lab-grown cell lines, they took cells directly from patients. Thats where they found SIRP-alpha.

Whats more, the UCSF team discovered that NK cells begin to express SIRP-alpha after they are activated by cytokines that are typically abundant in inflammatory states.

RELATED: Fierce Biotech's 2020 Fierce 15 | Sana Biotechnology

To further prove out the utility of engineered stem cells, the UCSF researchers implanted cells with rhesus macaque CD47 into monkeys. They documented the activation of SIRP-alpha in NK cells. Those NK cells did not kill the transplanted cells.

A similar technique could be used, but in reverse, to implant pig cardiac cells into people, the UCSF team argued. If human CD47 were engineered into pig heart cells, they could be implanted into people without risking rejection by NK cells, they suggested.

Sana made waves in 2018 when it raised a whopping $700 million in a single venture round from the likes of Arch Venture Partners, Flagship Pioneering and Bezos Expeditions. We believe that one of, if not the most, important thing happening in medicine over the next several decades is the ability to modulate genes, use cells as medicines, and engineer cells, said Steve Harr, president and CEO of Sana, at the time.

Sana did not provide materials or funding for the new study, but it is now developing the hypoimmune stem cell technology for clinical testing.

The UCSF team believes their findings could also boost cancer immunotherapy. The engineered cells could help combat checkpoints that allow tumors to evade immune detection, they said.

"Many tumors have low levels of self-identifying MHC-I protein and some compensate by overexpressing CD47 to keep immune cells at bay," said Lewis Lanier, Ph.D., director of the Parker Institute for Cancer Immunotherapy at the UCSF Helen Diller Family Comprehensive Cancer Center, in a statement. "This might be the sweet spot for antibody therapies that target CD47."

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Engineered stem cells that evade immune detection could boost cell therapy and I-O - FierceBiotech

At the end of the study, it was found that the rats had regained their ability to use their paws and were able to pick up sugar cubes to feed themselves, according to The Independent. The gene therapy trial was conducted at Kings College London, U.K. The focus of the work was to repair damage to the spinal cords of the rodents. The spinal cords of the rats had been purposefully damaged to mimic the damaged sometimes suffered to humans after car crashes. Quoted by Sky News, Professor Elizabeth Bradbury, one of the principal researchers, stated: "In some of the tests we looked at such as gripping the rungs of a ladder the treatment worked within one to two weeks."Gene therapyGene therapy is an important aspects of medicine. The process is designed to introduce genetic material into cells. This is to compensate for abnormal genes or, alternatively, to produce a beneficial protein. In cases where a mutated gene causes a necessary protein to be faulty or to become missing, then gene therapy could work to introduce a normal copy of the gene and hence to restore the function of the protein.There are different variants of gene therapy, including plasmid DNA, where circular DNA molecules are genetically engineered so they carry therapeutic genes into human cells; viral vectors, where viruses are used to deliver genetic material into cells; bacterial vectors, where bacteria are modified and then deployed as vehicles to carry therapeutic genes into human tissues; and human gene editing technology, where genes are edited to disrupt harmful genes or to repair mutated genes. There is also patient-derived cellular gene therapy products. With this more recent process, cells are taken from the patient, modified and then returned to the patient.For some scientists, the next phase is germinal gene therapy. This has been achieved experimentally in animals but not in humans.Novel researchWith the new study, the process involved injecting a gene that produces an enzyme called chondroitinase, into the spinal cords of the rats. This enzyme functions to breaks down scar tissue, a tissue that is formed following damage to the spinal cord. he tissue prevents new connections from being formed between nerves. The enzyme is also being used in trials for vitreous attachment and for treating cancer.

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article image Advances in gene therapy to help paralysis - Digital Journal

SAN DIEGO and STOCKHOLM, Sweden, Jan. 07, 2021 (GLOBE NEWSWIRE) -- Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, today announced that it established a research and development collaboration with world-renowned Karolinska Institutet in Stockholm, Sweden, to advance novel ROR1-targeting cell therapies focused on CAR-T cells and CAR-NK (Natural Killer) cells from the laboratory into the clinic.

As part of the collaboration, IND-supporting preclinical studies will be performed in the Cell and Gene Therapy Group led by Evren Alici, M.D. Ph.D., within the NextGenNK Center, which is a Competence Center for the development of next-generation NK cell-based cancer immunotherapies. The Center is coordinated by Karolinska Institutet and collaborates with the Karolinska University Hospital as well as prominent national and international industrial partners. The Center was launched in 2020, and is jointly funded by Swedens innovation agency Vinnova, Karolinska Institutet, and the industrial partners.

Given that NK cells were discovered at Karolinska Institutet, we are excited to work together with industry partners to translate scientific advances into next-generation cell therapies that will benefit cancer patients, said Hans-Gustaf Ljunggren, M.D. Ph.D., Director of the NextGenNK competence center. We look forward to collaborating with the outstanding team at Oncternal to develop cutting-edge T and NK cell therapies targeting ROR1, which is a promising target in many oncology indications. It could be ideally suited for cell therapy.

We are honored to work together with the world-leading academic team at Karolinska Institutet to accelerate the development of our ROR1-targeting CAR-T cell immunotherapy program, said James Breitmeyer, M.D., Ph.D., Oncternals President and CEO. ROR1 has emerged as an important and underexplored target for cancer therapy, and we believe that ROR1-targeting CAR-T and CAR-NK therapies hold significant promise for patients with both hematologic cancers and solid tumors. We believe that utilizing the ROR1 binding domain of our clinical-stage antibody cirmtuzumab as a component of the CAR has the potential to give us a safety and efficacy advantage.

About Oncternal TherapeuticsOncternal Therapeutics is a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies for the treatment of cancers with critical unmet medical need. Oncternal focuses drug development on promising yet untapped biological pathways implicated in cancer generation or progression. The clinical pipeline includes cirmtuzumab, an investigational monoclonal antibody designed to inhibit the ROR1 (Receptor-tyrosine kinase-like Orphan Receptor 1) pathway, a type I tyrosine kinase-like orphan receptor, that is being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) and in an investigator-sponsored, Phase 1b clinical trial in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer. The clinical pipeline also includes TK216,an investigational targeted small-molecule inhibitor of the ETS family of oncoproteins, that is being evaluated in a Phase 1 clinical trial for patients with Ewing sarcoma alone and in combination with vincristine chemotherapy. In addition, Oncternal has a program utilizing the cirmtuzumab antibody backbone to develop a CAR-T therapy that targets ROR1, which is currently in preclinical development as a potential treatment for hematologic cancers and solid tumors. More information is available at http://www.oncternal.com.

About KarolinskaInstitutetKarolinska Institutetis one of the worlds leading medical universities. Its vision is to advance knowledge about life and strive towards better health for all. Karolinska Institutet accounts for the single largest share of all academic medical research conducted in Sweden and offers the countrys broadest range of education in medicine and health sciences. The Nobel Assembly at Karolinska Institutet selects the Nobel laureates in Physiology or Medicine.

Forward-Looking InformationOncternal cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as may, will, should, expect, plan, anticipate, could, intend, target, project, contemplates, believes, estimates, predicts, potential or continue or the negatives of these terms or other similar expressions. These statements are based on the companys current beliefs and expectations. Forward looking statements include statements regarding Oncternals beliefs, goals, intentions and expectations including, without limitation, Oncternals belief that ROR1-targeting CAR-T and CAR-NK therapies hold significant promise for patients with hematologic cancers and solid tumors; whether using ROR1 binding domain as a component of the CAR therapeutic candidate will provide a safety or activity advantage over other drugs or drug candidates; the potential that ROR1 could be an ideal target for cell therapy; and other statements regarding Oncternals development plans. Forward looking statements are subject to risks and uncertainties inherent in Oncternals business, which include, but are not limited to: the risk that the collaboration with Karolinska Institutet will not generate any intellectual property or otherwise identify drug candidates for development or provide Oncternal any benefits; the COVID-19 pandemic may disrupt Oncternals business operations or the business operations of Karolinska Institutet, increasing their respective costs; uncertainties associated with the clinical development and process for obtaining regulatory approval of product candidates, including potential delays in the commencement, enrollment and completion of clinical trials; Oncternals dependence on the success of cirmtuzumab, TK216 and its other product development programs; the risk that competitors may develop technologies or product candidates more rapidly than Oncternal, or that are more effective than Oncternals product candidates, which could significantly jeopardize Oncternals ability to develop and successfully commercialize its product candidates; Oncternals limited operating history and the fact that it has incurred significant losses, and expects to continue to incur significant losses for the foreseeable future; the risk that the company will have insufficient funds to finance its planned operations and may not be able to obtain sufficient additional financing when needed or at all as required to achieve its goals, which could force the company to delay, limit, reduce or terminate its product development programs or other operations; and other risks described in the companys prior press releases as well as in public periodic filings with the U.S. Securities & Exchange Commission. All forward-looking statements in this press release are current only as of the date hereof and, except as required by applicable law, Oncternal undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

Oncternal Contacts:

Company ContactRichard Vincent 858-434-1113rvincent@oncternal.com

Investor ContactCorey Davis, Ph.D. LifeSci Advisors 212-915-2577 cdavis@lifesciadvisors.com

Source: Oncternal Therapeutics, Inc.

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Oncternal Therapeutics and Karolinska Institutet Establish Collaboration for Research and Development of ROR1-targeting CAR-T and CAR-NK Cell...

SAN FRANCISCO--(BUSINESS WIRE)--AllStripes (formerly RDMD), a healthcare technology company dedicated to accelerating research for patients with rare diseases, today announced a multiyear collaboration with Taysha Gene Therapies, Inc. (NASDAQ: TSHA), a patient-centric gene therapy company focused on developing and commercializing AAV-based gene therapies for the treatment of monogenic diseases of the central nervous system in both rare and large patient populations.

The collaboration will focus on advancing the development of TSHA-104, an AAV9-based gene therapy in development for SURF1-associated Leigh syndrome, a deadly rare disease that primarily affects infants. AllStripes will use its platform, which gives patients control over their health histories, to unify otherwise scattered and fragmented SURF1-associated clinical data, allowing researchers to uncover new insights into the natural history and burden of disease and better inform the development of clinical studies.

This collaboration will allow us to leverage the AllStripes technology platform to optimize our therapeutic strategy and to potentially accelerate the development of TSHA-104 in SURF1-associated Leigh syndrome, said RA Session, II, president, founder and chief executive officer of Taysha. We remain committed to developing a safe and effective gene therapy for patients suffering with this devastating disease, and data generated from this unique collaboration could bring us one step closer to our goal.

Mutations in the SURF1 gene prevent mitochondria from producing enough energy for cells in the body to function normally, leading to Leigh syndrome, a severe and rare neurological disorder characterized by progressive loss of mental and movement abilities. SURF1-associated Leigh syndrome typically presents during infancy or early childhood, and often results in death within a few years. Approximately 10-15% of people with Leigh syndrome have a SURF1 mutation. There is currently no targeted treatment or cure for SURF1-associated Leigh syndrome.

Taysha has brought together accomplished and knowledgeable gene therapy and CNS disease experts to develop potentially transformative therapies, said Nancy Yu, co-founder and chief executive officer of AllStripes. With no available treatment for SURF1-associated Leigh syndrome, we are very pleased to empower patients and their families with an avenue to participate in research that will support the development path of TSHA-104. We are hopeful that this novel gene therapy will bring meaningful benefit to children and their families, and give them more time together.

TSHA-104 has been granted rare pediatric disease and orphan drug designations from the U.S. Food and Drug Administration (FDA) for the treatment of SURF1-associated Leigh syndrome. An Investigational New Drug (IND) application for TSHA-104 in SURF1-associated Leigh syndrome is expected to be submitted to the FDA in 2021.

About Taysha Gene Therapies

Taysha Gene Therapies (Nasdaq: TSHA) is on a mission to eradicate monogenic CNS disease. With a singular focus on developing curative medicines, we aim to rapidly translate our treatments from bench to bedside. We have combined our teams proven experience in gene therapy drug development and commercialization with the world-class UT Southwestern Gene Therapy Program to build an extensive, AAV gene therapy pipeline focused on both rare and large-market indications. Together, we leverage our fully integrated platforman engine for potential new cureswith a goal of dramatically improving patients lives. More information is available at http://www.tayshagtx.com.

About AllStripes

AllStripes is a healthcare technology company dedicated to unlocking new treatments for people with rare diseases. AllStripes has developed a technology platform that generates FDA-ready evidence to accelerate rare disease research and drug development, as well as a patient application that empowers patients and families to securely participate in treatment research online and benefit from their own medical data. AllStripes was founded by CEO Nancy Yu and technology developer Onno Faber, following his diagnosis and journey with the rare disease neurofibromatosis type 2. The company is backed by Lux Capital, Spark Capital, Maveron Capital, Village Global, Garuda Ventures and a number of angel investors. For more information, visit http://www.allstripes.com.

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AllStripes Announces Collaboration with Taysha Gene Therapies for SURF1-Associated Leigh Syndrome Program - Business Wire

OTTAWA, Jan. 08, 2021 (GLOBE NEWSWIRE) -- The global regenerative medicine market is representing impressive CAGR of 16.1% during the forecast period 2020 to 2027.

Regenerative medicine is the division of medicine that promotes methods to repair, regrow or replace injured or diseased tissues, organs or cells. Regenerative medicine comprises of the formation and use of remedial stem cells, manufacturing of artificial organs, and tissue engineering. The combinations of tissue engineering, cell and gene therapies can strengthen the natural healing procedure in the places it is desired most, or occupy the role of a permanently injured organ. Regenerative medicine is a rather new field that connects experts in chemistry, biology, engineering, computer science, robotics, medicine, genetics and other domains to find explanations to some of the most interesting medical problems confronted by humankind.

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Growth Factors:

Factors such as increasing prevalence of chronic disorders and genetic disorders, increasing popularity of stem cells, increasing number of trauma emergencies is driving the growth of regenerative medicine market. An illness or disorder that usually persists for 3 months or longer and might get worse over a period is termed as chronic disorder. Chronic diseases mostly occur in the elderly people and can typically be controlled but not repaired. The most prevalent types of chronic ailments are heart disease, arthritis, cancer, diabetes, and stroke. Cardiovascular disorders are the biggest cause of deaths worldwide. As per the WHO data, deaths due to cardiovascular disorders represent almost 31% of the deaths globally. Almost 85% of these demises are due to stroke and heart attack. Diabetes is another most prevalent chronic ailment that affects millions of people globally. According to International Diabetes Federation (IDF), around 463 million adults (age group: 20-79 years) are battling with diabetes and by the year 2045 the number will rise to a staggering 700 million. Furthermore, approximately 75% of all health care expenses are owed to chronic ailments. Four out of the five most costly health conditions are chronic disorders such as cancer, heart disease, pulmonary conditions, and mental disorders. Regenerative medicine approaches such as stem cell therapy can cure the chronic ailments such as diabetes and arthritis, which otherwise require lifetime of medications.

The role of regenerative medicine in post trauma recovery is constantly evolving as more and more research is showing positive results. The use of regenerative medicine can be a landmark moment in the history of healthcare that will transform the treatment of chronic ailments and trauma related conditions. Thus, the high incidence of chronic ailments is driving the growth of regenerative medicine market.

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Regional Analysis:

The report covers data for North America, Europe, Asia Pacific, Latin America, and Middle East and Africa. In 2019, North America dominated the global market with a market share of more than 45%. U.S. represented the highest share in the North American region primarily due to constant activity in the field of drug discovery and tissue engineering. Moreover, early adoption of latest healthcare technologies also contributed to the high market share of the United States.

Europe was the second important market chiefly due to favorable reimbursement scenario and presence of latest healthcare infrastructure. The presence of skilled researchers in the European region is also expected to boost the demand for regenerative medicine market in the near future. Asia Pacific is anticipated to grow at the maximum CAGR of around18% in the forecast period due to high incidence of trauma cases and chronic disorders. Latin America and the African and Middle Eastern region will display noticeable growth.

Report Highlights:

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Key Market Players and Strategies:

The major companies operating in the worldwide regenerative medicine are Integra Life Sciences Corporation, Aspect Biosystems, Amgen, Inc., Medtronic plc, AstraZeneca, Novartis AG, Smith & Nephew plc, MiMedx Group, Shenzhen SibionoGeneTech Co., Ltd., and Baxteramong others.

High investment in the research and development along with acquisition, mergers, and collaborations are the key strategies undertaken by companies operating in the global regenerative medicine market. Recently Fuse Medical, Inc., an evolving manufacturer and supplier of innovative medical devices for the spine and orthopedic marketplace, declared the launch of FuseChoice Plus and FuseChoice Umbilical and Amniotic Membranes, and FuseChoice Plus Amniotic Joint Cushioning Fluid, the newest additions to a wide-ranging line of biologics product offerings.

Market Segmentation

By Product

By Application

By Geography

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Regenerative Medicine Market to Reach Valuation US$ 23.7 Bn by 2027 - GlobeNewswire

Dublin, Jan. 06, 2021 (GLOBE NEWSWIRE) -- The "Cell and Gene Therapy Global Market Report 2020-30: COVID-19 Growth and Change" report has been added to ResearchAndMarkets.com's offering.

Cell and Gene Therapy Global Market Report 2020-30: COVID-19 Growth and Change provides the strategists, marketers and senior management with the critical information they need to assess the global cell & gene therapy market.

Major players in the cell and gene therapy market are Gilead Sciences, Bristol-Myers Squibb, Novartis AG, Amgen, Merck, Organogenesis Holdings, Dendreon, Vericel, Bluebird Bio and Fibrocell Science.

The global cell and gene therapy market is expected to decline from $6.68 billion in 2019 to $6.92 billion in 2020 at a compound annual growth rate (CAGR) of 3.61%. The slow growth is mainly due to the COVID-19 outbreak that has led to restrictive containment measures involving social distancing, remote working, and the closure of industries and other commercial activities resulting in operational challenges. The entire supply chain has been disrupted, impacting the market negatively. The market is then expected to recover and reach $13.23 billion in 2023 at a CAGR of 24.10%.

The cell and gene therapy market consists of sales of cell and gene therapies by entities (organizations, sole traders and partnerships) that develop cell and gene therapies. Cell therapy refers to the transfer of intact, live cells that are originated from autologous or allogenic sources and gene therapy refers to the introduction, removal, or change in the genome for treating diseases. The market consists of revenue generated by the companies developing cell and gene therapy products by the sales of these products.

North America was the largest region in the cell and gene therapy market in 2019. It is also expected to be the fastest-growing region in the forecast period.

In December 2019, Roche, a Swiss multinational healthcare company, acquired Spark Therapeutics for $4.3 billion. The acquisition supports the commitment of Roche to bring transformational therapies and innovative approaches to people with serious illnesses. Spark Therapeutics will continue to work within the Roche Group as an independent company. Spark Therapeutics, headquartered in Philadelphia, is a fully integrated commercial company involved in the discovery, production, and distribution of gene therapies for genetic disorders including blindness, hemophilia, lysosomal storage, and neurodegenerative diseases.

The cell and gene therapy market covered in this report is segmented by product into cell therapy; gene therapy and by application into oncology; dermatology; musculoskeletal; others.

Limited reimbursements preventing patients from receiving treatments are expected to limit the growth of cell and gene therapy (CGT market. In 2019, Trinity Life Sciences, a life sciences solution provider, researched national and large regional commercial health insurance plans in the US. It found that the confluence of increasing price, patient volume and number of CGTs on the market is likely to change the reimbursement model for CGTs and impact payer budgets by 5-10%. Payers realize that financing needs to be generated for cost management due to the uncertainty surrounding reimbursement of ancillary costs. Limited reimbursements and uncertain insurance plans are preventing patients from receiving high-cost CGT, which is expected to limit market growth.

Chimeric antigen receptor (CAR) T-cell therapy is shaping the cell and gene therapy (CGT) market. (CAR) T-cell therapy is a combination of cell and gene therapy in which T cells are collected from the patient's blood and are genetically engineered to produce modified receptors at their surface, known as chimeric antigen receptors (CARs). These modified T cells with special structures (receptors) are reinfused into the patient. Then, the modified receptors of T cell help in targeting the surface antigen of the cancer cell that ultimately results in the killing of tumor cells in patients.

In 2020, the US-FDA approved Bristol-Myers Squibb's two CAR-T cell therapies to treat lymphoma and multiple myeloma and is set to be launched. Currently, FDA approved CAR-T cell therapy treatments like Tisagenlecleucel for the treatment of B-cell precursor acute lymphoblastic leukemia (ALL) in children and Axicabtagene ciloleucel for the treatment of adult patients with relapsed or refractory large B-cell lymphoma.

Steady investment and consolidation in cell and gene therapies contributed to the growth of the cell and gene therapy (CGT) market. After recognizing the potential of the CGT market, 16 out of the 20 largest biopharma companies by revenue, added CGT products to their portfolio.

Key Topics Covered:

1. Executive Summary

2. Cell And Gene Therapy Market Characteristics

3. Cell And Gene Therapy Market Size And Growth 3.1. Global Cell And Gene Therapy Historic Market, 2015 - 2019, $ Billion 3.1.1. Drivers Of The Market 3.1.2. Restraints On The Market 3.2. Global Cell And Gene Therapy Forecast Market, 2019 - 2023F, 2025F, 2030F, $ Billion 3.2.1. Drivers Of The Market 3.2.2. Restraints On the Market

4. Cell And Gene Therapy Market Segmentation 4.1. Global Cell And Gene Therapy Market, Segmentation By Product, Historic and Forecast, 2015-2019, 2023F, 2025F, 2030F, $ Billion

4.2. Global Cell And Gene Therapy Market, Segmentation By Application, Historic and Forecast, 2015-2019, 2023F, 2025F, 2030F, $ Billion

5. Cell And Gene Therapy Market Regional And Country Analysis

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/yvp1rq

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

Link:
Global Cell and Gene Therapy Market Report 2020-2030: COVID-19 Impacts, Growth and Changes - GlobeNewswire

The hunt for effective therapies for solid tumors has heated up in early 2021 with a string of biotechs touting big investor checks and name-brand collaborations to chase those hard-to-treat lumps. Now, with one of its candidates already in the clinic for leukemia, Mana Therapeutics is taking a new round of funding to join the fray.

On Friday, Mana unveiled a $35 million Series A financing round that will help push the Boston-area biotechs lead candidate through a Phase I trial and could help the company secure an IND for an off-the-shelf allogeneic molecule targeting transplant-ineligible AML and solid tumors within the year.

The biotechs leading molecule, dubbed MANA-312, is already engaged in the Phase I study of patients with acute myeloid leukemia, myelodysplastic syndrome after undergoing an allogenic hematopoietic stem cell transplantation. Manas goal is to use its technology to create an inventory of off-the-shelf allogeneic products that can treat the majority of patients with certain targeted cancer indications using whats called a human leukocyte antigen matching system.

Its a different take on a similar line of attack for solid tumors: using the bodys natural immune system to educate healthy cells already in the body to target antigens on the surface of the tumors cancer cells without damaging the otherwise healthy cells. To do this, Mana uses an in-house platform called EDIFY, which it says leverages natural immune system pathways to educate T cells to target multiple cell surfaces and intracellular tumor-associated antigens.

Through multiple antigen targeting processes, the companys technology is designed to prevent the tumors immune escape, and it says the allogeneic method which uses healthy donor cells to create a master cell bank and is then used for specific therapies of attacking the solid cancer tumors could provide superior efficacy to single antigen and other cell therapy approaches.

MANA-312 also isnt the biotechs only candidate in the works. MANA-412 is a preclinical off-the-shelf allogeneic cell therapy for treating transplant-ineligible acute myeloid leukemia and solid tumors and could be ready for an IND filing by the end of the year, Mana said. The Series A round will help fund preclinical development for that candidate as well.

Mana was founded based on research and human proof-of-concept clinical trials conducted by Catherine Bollard of Childrens National Hospital and her colleagues at Johns Hopkins Medical Center. Those trials, in both solid and hematologic tumors, supported a strong safety profile, showed immunological anti-tumor activity and validated MANAs initial set of tumor antigens, the company said. Then Bollard co-founded the company with industry vet Marc Cohen. Ex-Gilead exec Martin Silverstein is the CEO.

The human proof-of-concept trials conducted by my team and colleagues showed potential for a nonengineered approach to educating T-cells to attack multiple tumor antigens, which MANA is expanding even further through refinement of the manufacturing process for an allogeneic product and application to a broader set of antigens in a variety of clinical indications and settings, Bollard said in a statement.

MANAs $35 million financing round was led by Cobro Ventures and Lightchain Capital and joined by LifeSci Venture Partners with other undisclosed investors.

See the original post:
Mana joins the hectic fight against solid tumors with an 'off-the-shelf' candidate angling for an IND this year - Endpoints News

Dive Brief:

As the name suggests, biomolecular condensates are tiny concentrations of molecules found inside cells. Scientists have observed these clusters, which take the form of liquid-like droplets, for decades, but only recently determined that they help regulate cellular reactions and activities.

Like other cell-managing structures, researchers suspect that biomolecular condensates can give rise to a variety of diseases if they malfunction. This thinking has led to the formation of several new drug companies in the last couple years, with Dewpoint being the first to come out of stealth mode.

Dewpoint arrived in early 2019, backed by the venture capital firm Polaris Partners and a string of other investors. Company leadership said the initial focus would be cancer and neurodegenerative diseases, though other areas like immunology and infectious disease also appear to be on Dewpoint's radar. The Boston-based biotech quickly drew interest from pharmaceutical giants, too, with Bayer and Merck & Co. inking separate deals potentially worth $100 million or more.

With the Pfizer deal, Dewpoint joins a handful of companies targeting DM1. Audentes Therapeutics, a gene therapy developer now owned by Astellas, has been exploring two approaches to treat the disease. Vertex and CRISPR Therapeutics also recently expanded a gene editing partnership to include DM1 and Duchenne muscular dystrophy.

Faze Medicines has its sights set on DM1 as well. The Cambridge, Massachusetts-based biotech debuted in December with $81 million in Series A funding, which was supplied, in part, by some big pharmaceutical firms, including the Novartis Venture Fund and AbbVie Ventures.

Faze is also trying to find and develop treatments for ALS. Interim CEO Cary Pfeffer recently told BioPharma Dive that Faze may take aim at other neurological and neurodegenerative disorders, as well as cancer, immune diseases and viral illnesses.

See the original post:
Dewpoint forges another big pharma partnership and a potential rivalry - BioPharma Dive

A little less than two years after bagging an extended $50 million Series C, IsoPlexis and its proteomic barcodes for personalized cancer care are back setting hooks to bring even more investors on board. And this time, theyve caught a big fish.

Perceptive Advisors is leading a $135 million Series D round for the company, the firms announced Thursday, comprising $85 million in equity and a $50 million line of credit. IsoPlexis plans to use the proceeds to expand commercial and R&D staff, increase operational capacity and accelerate product development.

The Branford, CT-based company works with cancer centers and biopharma companies in the US, Europe and China, using its biomarker-driven system designed to predict responses to such treatments and personalize treatment for patients. IsoPlexis employs a proprietary single-cell analysis tool to refine its immunotherapies.

We believe the future of advanced medicines will rely upon deeper access to in vivo biology for the development of new therapies and are excited to back the team at IsoPlexis, Perceptive portfolio manager Sam Chawla said in a statement.

Researchers have developed what they call proteomic barcode chips, which allow them to look at the entire complement of proteins within a patients cells. Its a process they say provides the mapping of new and accessible layers of biological data for every single cell, ultimately allowing for a better understanding of how individuals may respond to therapies.

Essentially, patients receive samples of these chips, which CEO Sean Mackay says is barcoded with antibodies. After the company receives the sample back, they place it into their system to see just how a persons immune system would respond to different treatments.

We call that the single-cell immune landscaping, Mackay told Endpoints News. What were able to do with that is find subsets of powerful immune cells that you typically miss in bulk profiling, sort of status quo, and that is a product that works on our instrument, basically a software-enabled system that reads out what the chips look like and what the proteins are per cell.

That software then lets IsoPlexis compare whats typically missed in that bulk profiling to long-term responder patients in several different fields like cancer immunotherapy, cell and gene therapy, Covid-19 and autoimmune disease, among other areas. IsoPlexis can then pick and choose the appropriate preclinical treatments and biomarkers in the clinic, packaging that info to pharma companies and academic labs.

Perceptive, historically a passive investor that enjoys clinical-stage investments and crossover rounds, has been fairly busy over the last year or so. It made its first foray into the company formation and Series A spaces in late 2019, setting up a $210 million early-stage VC fund with Xontogeny. Then last August, they launched their first in-house start-up in China, followed by a $310 million raise a few months later. Perceptives third SPAC also filed for an IPO in late July.

Other new investors included Ally Bridge Group and funds and accounts managed by BlackRock. Unnamed existing investors also participated in the round.

Here is the original post:
IsoPlexis scores big backer for personalized protein 'barcodes' as Perceptive jumps on board new funding round - Endpoints News

LONDON--(BUSINESS WIRE)--The soft tissue repair market is poised to grow by USD 10.44 billion during 2020-2024, progressing at a CAGR of over 11% during the forecast period.

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The report on the soft tissue repair market provides a holistic update, market size and forecast, trends, growth drivers, and challenges, as well as vendor analysis.

The report offers an up-to-date analysis regarding the current global market scenario and the overall market environment. The market is driven by the rising incidence of accidental injuries.

The soft tissue repair market analysis includes Product segment and Geography Landscape. This study identifies the growing demand for gene therapy as one of the prime reasons driving the soft tissue repair market growth during the next few years.

This report presents a detailed picture of the market by the way of study, synthesis, and summation of data from multiple sources by an analysis of key parameters.

The soft tissue repair market covers the following areas:

Soft Tissue Repair Market SizingSoft Tissue Repair Market ForecastSoft Tissue Repair Market Analysis

Companies Mentioned

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Key Topics Covered:

Executive Summary

Market Landscape

Market Sizing

Five Forces Analysis

Market Segmentation by Product

Market Segmentation by Application

Market Segmentation by End-user

Customer landscape

Geographic Landscape

Vendor Landscape

Vendor Analysis

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Read more from the original source:
Global Soft Tissue Repair Market- Featuring 3M Co., Arthrex Inc., and Baxter International Inc. Among Others - Business Wire

In an effort to crack the code of hard-to-treat solid tumors, biopharma has tried numerous pathways to effectively target those masses without damaging healthy tissues. Phillys Carisma Therapeutics thinks it has a winner with its macrophage cell-based CAR-M candidates, and now its taking a new flush of investor cash to try one in the clinic.

Carisma has scored a $47 million Series B round to take its lead candidate, anti-HER2 CAR-M tumor fighter CT-0508, into a Phase I trial as well as advancing the rest of its preclinical macrophage pipeline. Carisma has keyed in on the use of targeted macrophage cells and vectors to penetrate the environment of solid cancer tumors without hurting health tissues a puzzle in the solid tumor field.

CT-0508s early-stage study will turn out the first human data for a CAR-M therapy based on those macrophage cells, Carisma said. CEO Steven Kelly told Endpoints News his company could offer an effective and safer way to target tumors and warm them up for the immune system to attack.

There are a number of characteristics about macrophages that would lend themselves towards applications of solid tumors and other indications, but what were focused on is solid tumors, Kelly said. Macrophages are preferentially recruited into a tumor microenvironment, and lymphocytes like the CAR-T approaches are actively excluded. So we think that we have an advantage by overcoming trafficking limitations to solid tumors.

This has been the sticking point for the industry: therapeutics that can invade the walls which surround cancerous tumors without damaging otherwise healthy cells.

Kelly is confident that Carismas technology will ultimately decipher how to do just that.

Once it starts eating (the cancerous tumor cells), the macrophages will start producing cytokines that effectively warm up that environment and convert an immunologically cold tumor into a warm or hot tumor and recruit in other cells, like T cells for example. So that last element is really unique to macrophages due to the antigen presentation capability, he said. They engage in cells directly, they warm up the tumor microenvironment, and they generate a true adaptive immune response. Thats how we think of ourselves and how were differentiated in the cell therapy space.

Kelly said it was a bit premature to know when Carisma would begin public readouts of the data surrounding its macrophage therapeutics, but he hoped they would be able to do so by the middle of this year.

The total capital Carisma has raised since its Series A financing in 2018 now totals roughly $109 million, and is a key step in moving the company from effectively a discovery-stage company to a clinical-stage company, Kelly said.

A lot of effort has gone into building this company. We had to transition from a bench project at (the University of) Penn, we had to demonstrate all the things necessary to get an IND declared (so) safety and efficacy we had to develop a GMP manufacturing process, Kelly said. All those were effectively developed to FDA satisfaction, and were moving into the clinic now.

Investors in the Series B financing are led by Symbiosis II, with subsequent investment from Solasta Ventures and Livzon Pharmaceutical Group. Additionally, Carisma said, existing investors AbbVie Ventures, HealthCap, Wellington Partners, IP Group, TPG Biotech, Agent Capital, and MRL Ventures Fund contributed to the new round of funding.

Read more from the original source:
Looking to solve the solid tumor puzzle box, Carisma aims to take 'CAR-M' groundbreaker into early-stage trial - Endpoints News

Investors like to see big plans, and Kevin Judice has plenty. The DiCE Molecules CEO is plotting a clinical trial launch for the biotechs lead small molecule for psoriasis and wants to double the staff in the next year and a half.

On Friday, those big plans landed him an $80 million Series C round.

Were very excited about it, he said of the raise led by RA Capital Management.

The round comes around two years after a $50 million Series B. While the B round was used for optimizing technology and building a pipeline, Judice says the Series C will propel the biotechs IL-17 antagonist to the clinic and fund the development of two other undisclosed programs.

This new capital allows us to expand our reach and get at more targets and have more opportunities to make high impact, Judice said.

DiCEs development process revolves around its DNA-encoded library. Such libraries allow researchers to screen millions even billions of compounds in parallel, using DNA tags that Judice compared to barcodes, which tell you what the constituent pieces of a molecule are.

Usually you do some kind of screen, like a high-throughput screen, or a DNA-encoded library screen, something like that, and you get a few hits. And then theres a long phase of just lab chemistry, where youre making individual compounds and trying to progress those hits, those initial binders, to something thats closer to a drug, Judice said.

That hit-to-lead phase is typically labor-intensive and slow, the CEO said. But DiCEs approach accelerates that work by using a smaller DNA-encoded library much smaller but richer in information, Judice said to screen in different ways after getting a hit.

What were actually looking for is the difference between just binding and something that is functional, Judice said.

DiCEs lead program is an agonist for cytokine receptor IL-17, which is implicated in diseases like psoriasis and psoriatic arthritis. Current antibody treatments targeting IL-17 are quite effective at treating psoriasis, but they are injectable and lack in convenience. DiCEs candidate would be oral, and the biotech is hoping to top the efficacy of Amgens already approved oral PDE4 inhibitor Otezla.

What were working on is an oral that will work as well as the anti-IL-17 antibodies. So it combines the convenience and safety of something like Otezla with the efficacy of an antibody like Cosentyx, Judice said. The antibodies tell us that IL-17 is exactly the right target.

Since 2017, DiCE has grown from a seven-person, peanut-sized company to a 29-person staff. And in the next 18 months, Judice is looking to bring that number to 58. The biotech inked a $2.3 billion discovery pact with Sanofi years ago, and is currently partnering with them on an I-O small-molecule program that Judice says isnt far behind the IL-17 candidate.

We should be ready to go public with more data on earlier programs over the course of the next 12 months. And then Im really excited about the opportunity to grow the pipeline by adding new programs to it, he said. Thats one of the things that is particularly great, from my perspective, about having RA Capital lead this round.

In addition to RA, Eventide Asset Management, New Leaf Venture Partners, Soleus Capital, Driehaus Capital Management, Osage University Partners and Asymmetry Capital Management, Northpond Ventures, Sands Capital, Sanofi Ventures, Alexandria Venture Investments, Altitude Ventures and Agent Capital also chipped into the Series C.

Here is the original post:
DiCE gets its 'library' card ready as it speeds development of DNA database-derived molecules with more investor cash - Endpoints News

By my calculations, Ive gone for treatment a total of 112 times in the past 6 years. Ive had approximately 23 scans, give or take a few due to brain scans, Ive had my heart checked at least 20 times, and blood draws somewhere around 30 times. Add to that oncologist appointments, primary care appointments, mental health appointments, a brief (but impactful) stint in physical therapy, as well as appointments Ive forgotten, and it becomes very clear to me why I struggle with the idea of celebrating a cancerversary that falls during the period of making New Years resolutions.

Like birthdays, Im counting up but there is a lot of the bittersweet when it comes to cancer milestones. I am thrilled to have lived a remarkable six years with metastatic breast cancer, but theres not a lot Ive forgotten about the first year following my diagnosis. It was a steep learning curve featuring fear, loss and gradual understanding along the way.

And yet, with six years in the rearview mirror, the road in front is still mostly the same for all of us. The number of people dying each year from metastatic breast cancer in the United States remains tragically high at over 40,000. The length of those lives at diagnosis remains mostly short. Just 27% of women with metastatic breast cancer and 22% of men are alive at five years from the date of their diagnosis. Theres been progresstoo often in the form of drugs that are so rough on our bodies that some choose to forgo them for the short life extension they promisebut theres been so much pain as well. Its hard to celebrate being here when friends have died far too soon or are facing the end of their treatment options.

Yet, the hope of the cancerversary is real this year.

I look back at my six years of metastatic breast cancer and thereve been two high school graduations with a third on the horizon, a college graduation, good times with good friends and trips to see the people I love. Ive packed a lot into six years and felt it all, good and bad. Year seven, starting at the same time as enormous changes in our country including a new President, new vaccines for COVID-19, renewed hope, seems like the right time to take note of a full six years of life when what I expected at the start was so much less.

So, while Im not fully celebrating, I am aware of all that I would have missed. I am spending this month in thanks for the people whove kept me here, from my friends to my oncologist to the researchers whove put their careers directly in my unplanned path. I am acknowledging the fear I felt that lingers and the love that encircles me even when we cant give one another hugs. Life is short and it is often far shorter with cancer.

Year 7 may be too much like Year 6, where months of doing so very little other than what was devoted to cancer sometimes made it feel endlessly empty, but somehow the future seems to be stretching out in front of me in this moment. Acknowledging a cancerversary in the midst of this particular new year seem like the proper expression of hope. Heres to my Year 7 and to 2021may it be good to us all.

Originally posted here:
Looking At Year Seven On This Cancerversary - Curetoday.com

Sustaining production from mature brownfields is becoming an uphill task in the current storm of pandemic plus economic crisis. In this years papers on mature fields and well revitalization, I have found operators focusing on making all-out efforts to improve their ongoing waterflood operations to extend the life of existing wells, which is preferred over drilling new infill wells.

Waterflooding is the oldest method used for secondary recovery in oil fields because water is readily available and relatively inexpensive. Although the concept behind waterflooding is relatively simple and easy to implement, the reality is different, with many potential challenges such as water circulation because of poor reservoir conformance, induced matrix fracturing resulting in early water breakthrough, and reservoir souring, to mention just a few. The older the waterflood, the more susceptible it becomes to problems and challenges, and the most unavoidable challenge is managing increased amounts of produced water.

A third of the papers studied this year focus on improved-/enhanced-oil-recovery techniques, and a majority of them focus on improving waterfloods through various techniques such as using classical analysis and data-driven technologies for redistributing injected water and integrating efforts with cross-disciplinary teams.

Another area of focus is extending the life of existing wells. It is both a challenge and an opportunity. It is a challenge because operators must find a delicate balance between extending the life of an old well and jeopardizing the safety and integrity conditions in the field. It is an opportunity because it provides an attractive alternative for identifying and appraising possible behind-casing opportunities before plugging and abandonment. Several studies have been conducted to identify and appraise such opportunities.

Natural Dumpflood in Malaysia Succeeds as Low-Cost Offshore Oil-Recovery Method

Fracturing With Height Control Extends the Life of Mature Reservoirs in the Pannonian Basin

Analytical Work Flows Enable Continuous Waterflooding Optimization for a Mature Field

IPTC 19763 Chasing Behind-Casing Opportunities in Low-Salinity Laminated Brown Reservoirs by Noor Faezah Ramly, Petronas, et al.

SPE 199205 Standardization of Inactive Wells-Audit Process for Well Abandonment and Production Enhancement Candidate Screening by Elin Haryanto, Schlumberger, et al.

SPE 197474 Prevention of Well-Control Incidents and Well Life Extension in Mature Fields by Andrey Yugay, ADNOC, et al.

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JPT Mature Fields and Well Revitalization - Journal of Petroleum Technology

WASHINGTON The first full year for the U.S. Space force marked an eventful stretch for the military in space.

From the growth of the nascent military branch to the award of massive new launch contracts, 2020 was a busy year in the space domain. Just this December, the Trump administration formalized its thinking about space in a new National Space Policy and gave Space Force members a surprise birthday gift: an official name. With new developments, launches and announcements spilling out throughout this year, even the most ardent observers could be forgiven for missing a story or two.

And so without any more bloviating heres a recap of the top six military space stories of 2020.

The Space Force takes shape

While history will note 2019 as the year the Space Force was created, 2020 was the year the new service began to take shape.

Chief of Space Operations Gen. John Jay Raymond says his team had five focus areas for year one of setting up the first new branch of the military in 70 years: developing its people, developing its doctrine, presenting an independent budget, designing the force and presenting forces to a joint command. Raymonds team has arguably made strides in all of those areas.

In 2020, the Space Force got its first member and chief of space operations, added 2,500 people to the new service, defined spacepower as distinct from military power in its capstone doctrine, set up the first of three commands, began implementing a series of acquisition reforms, and gave its personnel their official name: guardians. Questions remain, such as which capabilities and offices will transfer to the Space Force from the other services and what the new Space Systems Command will look like. Still, Raymond was optimistic about the progress made in year one.

As I look back on this first year, I look back with great pride great pride for the work that our space professionals have done in establishing this new service, said Raymond in a December media call. The progress we have made far surpasses anything I would have expected. We have completely reorganized the national security space organization the largest restructure in our history.

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Space Development Agency orders first satellites

When the Trump administration created the Space Development Agency in March 2019, the office was a bit of an enigma. While most observers called for the consolidation of space systems acquisitions, the Trump administration established a new agency outside the purview of the U.S. Air Force. Furthermore, experts questioned whether the agency would survive the year, especially with the establishment of a Space Force imminent.

But in 2020, SDA defined its place in the nations space enterprise: building a new National Defense Space Architecture that will be made up of hundreds of satellites in low Earth orbit. The core of that architecture a space-based mesh network will serve as the space component of Combined Joint All-Domain Command and Control, the Pentagons effort to connect any sensor to any shooter across services and domains.

And while the agencys biggest advocate in the Pentagon Under Secretary of Defense for Research and Engineering Mike Griffin left the government for the private sector, the office moved forward confidently in soliciting and awarding its first contracts over the summer. In August, the agency awarded York Space Systems $94 million and Lockheed Martin $188 million to build 10 satellites each for the inaugural transport layer. Then in October, the agency issued contracts for its first eight missile tracking satellites: $149 million for SpaceX and $193 million for L3Harris. A protest from Raytheon Technologies is holding up the tracking layer satellites, though SDA says it is taking corrective action and working to keep the effort on track for a 2022 delivery.

SpaceX and ULA win massive launch contracts

In one sense, the story of 2020 could be the emergence and success of several small launch providers despite a global pandemic. Yet the biggest launch contract of the year was for traditional heavy launches. In August, the Space Force issued its National Security Space Launch contract to SpaceX and United Launch Alliance, with the former receiving $316 million and the latter receiving $337 million.

The National Security Space Launch contracts will support more than 30 heavy lift launches for the Space Force and National Reconnaissance Office over a five-year period from fiscal 2022 through 2027. Under the arrangement, 60 percent of launch services orders will go to ULA, with SpaceX taking up the remainder.

While the award is a major victory for SpaceX, which has fought tooth and nail to force its way into the lucrative military heavy lift launch market, it is undoubtedly frustrating for the two companies left out Northrop Grumman and Blue Origin which had been developing new rockets as part of the competition.

On-orbit servicing presents new opportunities

2020 marked the first successful docking of two commercial satellites on orbit as part of a commercial satellite life extension service offered by Northrop Grummans SpaceLogistics. That service involves attaching a SpaceLogistics Mission Extension Vehicle to an Intelsat communications satellite with depleted fuel reserves. By supplementing the satellites fuel reserves with its own and effectively towing the client around orbit, the MEV is expected to stretch the satellites service life by five years.

While the mission was entirely commercial, it has major implications for the military, which is looking into using SpaceLogistics services to extend the lives of its own satellites.

And commercial on-orbit satellite servicing could extend far beyond simply supplementing empty fuel reserves. Following the successful docking in February, SpaceLogistics announced a partnership with the Defense Advanced Research Projects Agency on the Robotic Servicing of Geosynchronous Satellites (RSGS) program, which is working to create the first commercial spacecraft with a robotic arm that can perform repairs, augmentation, assembly, inspection or relocation of other spacecraft already on orbit.

SpaceLogistics is understandably bullish about the prospect of the military purchasing life extension services, and the Department of Defense has expressed interest. Other companies are eager to compete to provide those services. Most notably, Astroscale entered the field in June, providing its own slate of on-orbit servicing solutions.

Perhaps on-orbit servicing wont be as feasible or cost effective as hoped, but 2020 was the year the concept became a reality.

Russia continues anti-satellite weapons testing

Throughout 2019 and 2020, the Pentagon used the development and testing of anti-satellite weapons by Russia and China as a justification for establishing the Space Force. And in 2020, Russia provided plenty of fodder for those who believe that nations space activities are provocative, to say the least.

In 2020, the Russian government conducted two tests of a direct-ascent anti-satellite missile, capable of taking out satellites in low Earth orbit. While Russia has tested such missiles in the past, pushback from the newly established U.S. Space Command brought the issue to the fore in 2020. The 11th combatant command was quick and direct in calling out the tests, which it characterized as aggressive.

Russias DA-ASAT test provides yet another example that the threats to U.S. and allied space systems are real, serious and growing, said Raymond, then-head of U.S. Space Command, after the first test in April. The United States is ready and committed to deterring aggression and defending the nation, our allies and U.S. interests from hostile acts in space.

The command continued its criticisms of Russia in December, when that government conducted another test.

Russia has made space a war-fighting domain by testing space-based and ground-based weapons intended to target and destroy satellites. This fact is inconsistent with Moscows public claims that Russia seeks to prevent conflict in space, Space Command head Gen. James Dickinson said. Space is critical to all nations. It is a shared interest to create the conditions for a safe, stable and operationally sustainable space environment.

But perhaps more concerning than the direct-ascent missiles was what USSPACECOM characterized as the testing of an on-orbit anti-satellite weapon. In July, USSPACECOM announced that a Russian satellite appeared to have launched a high-speed projectile into space, an action inconsistent with its stated purpose. A similar test was carried out in 2017.

U.S. officials have not shied away from characterizing this capability as a weapon especially since Russian government satellites have a habit of sidling up to U.S. commercial and government satellites.

China and Russia are continuing to develop space weaponry, said Vice President Mike Pence in December remarks to the National Space Council. Russia demonstrated a space-based anti-satellite weapon earlier this year. China is developing a new manned space station, and its robotic spacecraft will return samples from the moon in just a matter of weeks.

Army tests space-enabled sensor-to-shooter pipeline

Superficially, the Army doesnt scream space. Yet in 2020, the Army made big advances during Project Convergence that show how it plans to use new space-based capabilities to enable beyond-line-of-sight targeting.

Project Convergence is the Armys new campaign of learning, an effort to transform the battlefield with artificial intelligence, developmental networks and new sensing capabilities. In short, the Army wants to be able to connect any sensor to the best shooter. Satellites were used both as sensors to detect threats and as a network to connect sensors and shooters across the battlefield.

Tactical imagery satellites were a major part of Project Convergence. Taking images of the battlefield from their high vantage point, a satellite would downlink its data to a TITAN surrogate, where artificial intelligence was then used to process that imagery, automatically detect threats, and provide targeting data to Army shooters. In this new setup, satellites can provide the essential sensing capability to enable beyond-line-of-sight targeting.

The Army also tapped into new commercial satellite networks in low Earth orbit to connect its systems. Using proliferated constellations such as SpaceXs Starlink, the Army was able to transport data hundreds of miles in just seconds. Army officials say they will be able to experiment with even more capacity at Project Convergence 2021, as the commercial constellations become more mature.

All told, those space-based capabilities helped cut down the sensor-to-shooter timeline from 20 minutes to 20 seconds.

I can tell you with confidence, there isnt a person in the Army now who doesnt understand or isnt able to appreciate the capability that this deep sensing capability from space provides now, Willie Nelson, director of Army Futures Commands Assured Positioning, Navigation and Timing Cross-Functional Team, told C4ISRNET following the exercise. Theres not a dry eye in the room when you look at how fast we can rapidly find threats and get those to shooters.

Much, much more to come

Missing your favorite military space development of 2020? Perhaps you were more interested in the relaunch of the secretive X-37B space plane, the operational acceptance of M-Code Early Use, or even the completion of the Advanced Extremely High Frequency communications constellation. 2020 was a busy year to be sure, and 2021 looks to be equally enthralling as we learn about the Biden teams plans for the space domain, see how the Space Force organizes its acquisitions, and find out how the military will utilize emerging commercial space capabilities.

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The 6 big military space stories of 2020 - C4ISRNet

LOS ANGELES, United States: QY Research has recently published a research report titled, Global Magnolia Bark Extract Sales Market Report 2020. This report has been prepared by experienced and knowledgeable market analysts and researchers. It is a phenomenal compilation of important studies that explore the competitive landscape, segmentation, geographical expansion, and revenue, production, and consumption growth of the global Magnolia Bark Extract market. Players can use the accurate market facts and figures and statistical studies provided in the report to understand the current and future growth of the global Magnolia Bark Extract market.

The report includes CAGR, market shares, sales, gross margin, value, volume, and other vital market figures that give an exact picture of the growth of the global Magnolia Bark Extract market.

Competitive Landscape

Competitor analysis is one of the best sections of the report that compares the progress of leading players based on crucial parameters, including market share, new developments, global reach, local competition, price, and production. From the nature of competition to future changes in the vendor landscape, the report provides in-depth analysis of the competition in the global Magnolia Bark Extract market.

Key questions answered in the report:

TOC

1 Magnolia Bark Extract Market Overview1.1 Magnolia Bark Extract Product Scope1.2 Magnolia Bark Extract Segment by Type1.2.1 Global Magnolia Bark Extract Sales by Type (2020-2026)1.2.2 Solid Form1.2.3 Powder Form1.3 Magnolia Bark Extract Segment by Application1.3.1 Global Magnolia Bark Extract Sales Comparison by Application (2020-2026)1.3.2 Pharmaceutical1.3.3 Food and Beverages1.3.4 Others1.4 Magnolia Bark Extract Market Estimates and Forecasts (2015-2026)1.4.1 Global Magnolia Bark Extract Sales Growth Rate (2015-2026)1.4.2 Global Magnolia Bark Extract Revenue and Growth Rate (2015-2026)1.4.3 Global Magnolia Bark Extract Price Trends (2015-2026) 2 Magnolia Bark Extract Estimate and Forecast by Region2.1 Global Magnolia Bark Extract Market Size by Region: 2015 VS 2020 VS 20262.2 Global Magnolia Bark Extract Retrospective Market Scenario by Region (2015-2020)2.2.1 Global Magnolia Bark Extract Sales Market Share by Region (2015-2020)2.2.2 Global Magnolia Bark Extract Revenue Market Share by Region (2015-2020)2.3 Global Magnolia Bark Extract Market Estimates and Forecasts by Region (2021-2026)2.3.1 Global Magnolia Bark Extract Sales Estimates and Forecasts by Region (2021-2026)2.3.2 Global Magnolia Bark Extract Revenue Forecast by Region (2021-2026)2.4 Geographic Market Analysis: Market Facts & Figures2.4.1 United States Magnolia Bark Extract Estimates and Projections (2015-2026)2.4.2 Europe Magnolia Bark Extract Estimates and Projections (2015-2026)2.4.3 China Magnolia Bark Extract Estimates and Projections (2015-2026)2.4.4 Japan Magnolia Bark Extract Estimates and Projections (2015-2026)2.4.5 Southeast Asia Magnolia Bark Extract Estimates and Projections (2015-2026)2.4.6 India Magnolia Bark Extract Estimates and Projections (2015-2026) 3 Global Magnolia Bark Extract Competition Landscape by Players3.1 Global Top Magnolia Bark Extract Players by Sales (2015-2020)3.2 Global Top Magnolia Bark Extract Players by Revenue (2015-2020)3.3 Global Magnolia Bark Extract Market Share by Company Type (Tier 1, Tier 2 and Tier 3) (based on the Revenue in Magnolia Bark Extract as of 2019)3.4 Global Magnolia Bark Extract Average Price by Company (2015-2020)3.5 Manufacturers Magnolia Bark Extract Manufacturing Sites, Area Served, Product Type3.6 Manufacturers Mergers & Acquisitions, Expansion Plans3.7 Primary Interviews with Key Magnolia Bark Extract Players (Opinion Leaders) 4 Global Magnolia Bark Extract Market Size by Type4.1 Global Magnolia Bark Extract Historic Market Review by Type (2015-2020)4.1.1 Global Magnolia Bark Extract Sales Market Share by Type (2015-2020)4.1.2 Global Magnolia Bark Extract Revenue Market Share by Type (2015-2020)4.1.3 Global Magnolia Bark Extract Price by Type (2015-2020)4.2 Global Magnolia Bark Extract Market Estimates and Forecasts by Type (2021-2026)4.2.1 Global Magnolia Bark Extract Sales Forecast by Type (2021-2026)4.2.2 Global Magnolia Bark Extract Revenue Forecast by Type (2021-2026)4.2.3 Global Magnolia Bark Extract Price Forecast by Type (2021-2026) 5 Global Magnolia Bark Extract Market Size by Application5.1 Global Magnolia Bark Extract Historic Market Review by Application (2015-2020)5.1.1 Global Magnolia Bark Extract Sales Market Share by Application (2015-2020)5.1.2 Global Magnolia Bark Extract Revenue Market Share by Application (2015-2020)5.1.3 Global Magnolia Bark Extract Price by Application (2015-2020)5.2 Global Magnolia Bark Extract Market Estimates and Forecasts by Application (2021-2026)5.2.1 Global Magnolia Bark Extract Sales Forecast by Application (2021-2026)5.2.2 Global Magnolia Bark Extract Revenue Forecast by Application (2021-2026)5.2.3 Global Magnolia Bark Extract Price Forecast by Application (2021-2026) 6 United States Magnolia Bark Extract Market Facts & Figures6.1 United States Magnolia Bark Extract Sales Market Share by Company (2015-2020)6.2 United States Magnolia Bark Extract Sales Market Share by Type (2015-2020)6.3 United States Magnolia Bark Extract Sales Market Share by Application (2015-2020) 7 Europe Magnolia Bark Extract Market Facts & Figures7.1 Europe Magnolia Bark Extract Sales Market Share by Company (2015-2020)7.2 Europe Magnolia Bark Extract Sales Market Share by Type (2015-2020)7.3 Europe Magnolia Bark Extract Sales Market Share by Application (2015-2020) 8 China Magnolia Bark Extract Market Facts & Figures8.1 China Magnolia Bark Extract Sales Market Share by Company (2015-2020)8.2 China Magnolia Bark Extract Sales Market Share by Type (2015-2020)8.3 China Magnolia Bark Extract Sales Market Share by Application (2015-2020) 9 Japan Magnolia Bark Extract Market Facts & Figures9.1 Japan Magnolia Bark Extract Sales Market Share by Company (3015-3030)9.2 Japan Magnolia Bark Extract Sales Market Share by Type (2015-2020)9.3 Japan Magnolia Bark Extract Sales Market Share by Application (2015-2020) 10 Southeast Asia Magnolia Bark Extract Market Facts & Figures10.1 Southeast Asia Magnolia Bark Extract Sales Market Share by Company (2015-2020)10.2 Southeast Asia Magnolia Bark Extract Sales Market Share by Type (2015-2020)10.3 Southeast Asia Magnolia Bark Extract Sales Market Share by Application (2015-2020) 11 India Magnolia Bark Extract Market Facts & Figures11.1 India Magnolia Bark Extract Sales Market Share by Company (2015-2020)11.2 India Magnolia Bark Extract Sales Market Share by Type (2015-2020)11.3 India Magnolia Bark Extract Sales Market Share by Application (2015-2020) 12 Company Profiles and Key Figures in Magnolia Bark Extract Business12.1 Swanson12.1.1 Swanson Corporation Information12.1.2 Swanson Business Overview12.1.3 Swanson Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.1.4 Swanson Magnolia Bark Extract Products Offered12.1.5 Swanson Recent Development12.2 Samsara herbs12.2.1 Samsara herbs Corporation Information12.2.2 Samsara herbs Business Overview12.2.3 Samsara herbs Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.2.4 Samsara herbs Magnolia Bark Extract Products Offered12.2.5 Samsara herbs Recent Development12.3 Genesis Today12.3.1 Genesis Today Corporation Information12.3.2 Genesis Today Business Overview12.3.3 Genesis Today Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.3.4 Genesis Today Magnolia Bark Extract Products Offered12.3.5 Genesis Today Recent Development12.4 Planetary Herbals12.4.1 Planetary Herbals Corporation Information12.4.2 Planetary Herbals Business Overview12.4.3 Planetary Herbals Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.4.4 Planetary Herbals Magnolia Bark Extract Products Offered12.4.5 Planetary Herbals Recent Development12.5 Solaray12.5.1 Solaray Corporation Information12.5.2 Solaray Business Overview12.5.3 Solaray Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.5.4 Solaray Magnolia Bark Extract Products Offered12.5.5 Solaray Recent Development12.6 Active Herb12.6.1 Active Herb Corporation Information12.6.2 Active Herb Business Overview12.6.3 Active Herb Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.6.4 Active Herb Magnolia Bark Extract Products Offered12.6.5 Active Herb Recent Development12.7 LiftMode12.7.1 LiftMode Corporation Information12.7.2 LiftMode Business Overview12.7.3 LiftMode Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.7.4 LiftMode Magnolia Bark Extract Products Offered12.7.5 LiftMode Recent Development12.8 Life Extension12.8.1 Life Extension Corporation Information12.8.2 Life Extension Business Overview12.8.3 Life Extension Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.8.4 Life Extension Magnolia Bark Extract Products Offered12.8.5 Life Extension Recent Development12.9 thepurehealth12.9.1 thepurehealth Corporation Information12.9.2 thepurehealth Business Overview12.9.3 thepurehealth Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.9.4 thepurehealth Magnolia Bark Extract Products Offered12.9.5 thepurehealth Recent Development12.10 Hawaii Pharm LLC12.10.1 Hawaii Pharm LLC Corporation Information12.10.2 Hawaii Pharm LLC Business Overview12.10.3 Hawaii Pharm LLC Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.10.4 Hawaii Pharm LLC Magnolia Bark Extract Products Offered12.10.5 Hawaii Pharm LLC Recent Development12.11 Piping Rock Health Products12.11.1 Piping Rock Health Products Corporation Information12.11.2 Piping Rock Health Products Business Overview12.11.3 Piping Rock Health Products Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.11.4 Piping Rock Health Products Magnolia Bark Extract Products Offered12.11.5 Piping Rock Health Products Recent Development12.12 Now Foods Source Naturals12.12.1 Now Foods Source Naturals Corporation Information12.12.2 Now Foods Source Naturals Business Overview12.12.3 Now Foods Source Naturals Magnolia Bark Extract Sales, Revenue and Gross Margin (2015-2020)12.12.4 Now Foods Source Naturals Magnolia Bark Extract Products Offered12.12.5 Now Foods Source Naturals Recent Development 13 Magnolia Bark Extract Manufacturing Cost Analysis13.1 Magnolia Bark Extract Key Raw Materials Analysis13.1.1 Key Raw Materials13.1.2 Key Raw Materials Price Trend13.1.3 Key Suppliers of Raw Materials13.2 Proportion of Manufacturing Cost Structure13.3 Manufacturing Process Analysis of Magnolia Bark Extract13.4 Magnolia Bark Extract Industrial Chain Analysis 14 Marketing Channel, Distributors and Customers14.1 Marketing Channel14.2 Magnolia Bark Extract Distributors List14.3 Magnolia Bark Extract Customers 15 Market Dynamics15.1 Magnolia Bark Extract Market Trends15.2 Magnolia Bark Extract Opportunities and Drivers15.3 Magnolia Bark Extract Market Challenges15.4 Magnolia Bark Extract Market Restraints15.5 Porters Five Forces Analysis 16 Research Findings and Conclusion 17 Appendix17.1 Research Methodology17.1.1 Methodology/Research Approach17.1.2 Data Source17.2 Author List17.3 Disclaimer

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Comprehensive Report on Magnolia Bark Extract Market 2021 | Trends, Growth Demand, Opportunities & Forecast To 2027 - LionLowdown

The R/V Roger Revelle out at sea for a 10-day commissioning and calibration cruise following its midlife refit. Photo: Scripps Institution of Oceanography

Research vessel (R/V)Roger Revelleis back at work after a midlife refit involving upgrades from top to bottom, bow to stern. The primary goal of extending the service life by 15 to 20 years was accomplished with improvements to systems crucial to the vessels operations, scientific capabilities, habitability, and environmental footprint.

The ship is owned by the Office of Naval Research and has been operated by Scripps Institution of Oceanography at the University of California San Diego since 1996. It is one of the largest ships in the U.S. Academic Research Fleet, and vitally important to U.S. oceanographic research due to its range, payload, duration, and ability to safely conduct scientific operations in remote areas around the globe.

Roger Revelleisn't just revitalized, it is better than new, said Bruce Appelgate, associate director and head of ship operations at Scripps Oceanography. The midlife refit was an opportunity to apply everything we've learned about the ship since 1996, in order to make a great research vessel even more effective.

The $60 million refit, which includes the base refit cost and investment in scientific systems and instrumentation, was supported by the Office of Naval Research (ONR), National Science Foundation (NSF), and UC San Diego.

The partnership between the National Science Foundation and the Office of Naval Research in supporting the Global class vessels is one of the most important Federal alliances the Division of Ocean Science has made in safeguarding our critical sea-going science missions, said Rose Dufour, NSF Program Director.

Upgrades to R/VRoger Revelleinclude the addition of diesel engines that reduce emissions by up to two-thirds, ballast water systems designed to protect against the spread of invasive species, and the use of heat captured from the ships engine to desalinate seawater. These upgrades are the latest reflection of an ongoing effort throughout the U.S. Academic Research Fleet to reduce the environmental impact of ships.

An innovative extendable bow thruster has been installed that can be lowered beneath the ship to deliver thrust in any direction. This provides more power and quieter operations compared to the original bow thruster. Coupled with the ships dynamic positioning system, the new thruster enables it to maintain precise positioning and improves maneuverability when coming into port.

The ships overboard handling systems also got an overhaul, with new cranes and a completely refurbished A-frame and hydrographic boom used to deploy and recover scientific instruments while at sea.

Upgraded network capabilities support the significant amount of data collected from these instruments. A new virtual desktop infrastructure (VDI) includes display consoles for all systems throughout the ship, reducing the workload for scientists and crew members alike who use these during their operations. New cyberinfrastructure and centralized computer management helps the ships technicians maintain security and reliability of onboard computing and networking.

Another major upgrade was the addition of the acoustics gondola secured below the keel. This new position results in significantly improved sonar performance, enabling operations to continue even in high sea states. Acoustic systems are used to profile the subsurface, identify animals in the water column, track subsurface vehicles, and measure ocean currents. They are also used to map the seafloor, a capability much desired by the renewed effort to map the U.S. Exclusive Economic Zone through the Federal National Ocean Mapping, Exploration, and Characterization (NOMEC) Strategy, which NSF and ONR help lead.R/VRoger Revellewill now have the most sophisticated mapping capabilities in the U.S. Academic Research Fleet.

Inside the ships laboratories, reconfigurable tables feature an innovative nesting design that allows for practical and efficient use of space for scientists with a variety of needs. Improving the living and recreation spaces for everyone on board was important during the overhaul as well, particularly for crew members who make the ship their home for months at a time. Upgrades to living spaces include new carpets, bed curtains, and flooring.

The overhaul of the vessel was conducted in Portland, Ore., by Vigor Shipyard. R/VRoger Revellereturned to its home port of San Diego in July, where Scripps Oceanography technicians worked under UC San Diegos enhanced safety protocols to complete the work.

R/VRoger Revellewas put into service in 1996. It honors former Scripps Oceanography Director Roger Revelle who is widely regarded for not only establishing the institution as an internationally prominent science center, but for solidifying the decades-long relationship between Scripps Oceanography and the U.S. Navy.

Roger Revelle was a visionary who back in 1946 envisioned the Office of Naval Research as a world leader in sponsoring oceanographic basic research, and later foresaw the need for a new University of California in La Jolla that eventually grew around Scripps, said Tom Drake, director of the Ocean Battlespace and Expeditionary Access department at the Office of Naval Research. He also suggested the likely trajectory of the Earths climate, which we are now observing.

Revelle served as an oceanographer for the U.S. Navy during World War II and was instrumental in the founding of the Office of Naval Research. Roger Revelle worked at Scripps Oceanography before and after the war and served as its director from 1950 to 1964. He was among the first to consider the implications of the accumulation of carbon dioxide in the atmosphere and absorption rates of the greenhouse gas by the ocean.

A continuous profiling system under the ship will also measure carbon dioxide in seawater, an essential component of ocean acidification research.

"The revitalization of R/VRoger Revellewill enable even more scientific discoveries at sea to further our understanding of our planet, said Margaret Leinen, vice chancellor for marine sciences at UC San Diego and director of Scripps Oceanography. We appreciate the continued leadership from Congress to build and renovate the U.S. research fleet."

The first research expedition on the all-new R/VRoger Revellegot underway in early November, in an essential research mission led by UC Santa Barbara to retrieve ocean bottom seismometers measuring seismic activity and to collect rocks from seamounts and underwater volcanoes. The ship has already crossed the equator and is putting the upgraded acoustic systems to use while recovering these instruments.

Thesecond research cruise begins on Christmas day, during which R/VRoger Revelletravels to the Southern Ocean. The ships handling systems will be put through their paces as scientists collect samples, photographs, and sensor data to learn about plankton concentrations in eddies that form in the Southern Pacific. This 60-day expedition led by Barney Balch of theBigelow Laboratory for Ocean Scienceswill also deploy biogeochemical floats for theSouthern Ocean Carbon and Climate Observations and Modeling project, a multi-institution program focused on unlocking the mysteries of the Southern Ocean and determining its influence on climate.

While the enduring connection between the Navy and Scripps is manifest in the vessels namesake, this service life extension will serve multiple agencies, academic institutions and inspire the next generation of ocean-going scientists, said Rob Sparrock, program officer with the Office of Naval Research who oversees the research vessel program.

Appelgate said the refit illustrates the continued value of seagoing research vessels even as remote and autonomous observing platforms proliferate to compliment ship-based research.

Shipboard research offers the transformative potential to understand global change and monitor the health of ocean ecosystems, while training the next generation of sea-going scientists and technicians, Appelgate said.

The home port of R/VRoger Revelleis theNimitz Marine Facilityin San Diego, where the vessel is maintained as part of the Scripps oceanographic research fleet alongside the Navy-owned and Scripps-operated R/VSally Ride,the University of California-owned R/VRobert Gordon Sproul,R/VBob and Betty Beyster,and Research Platform FLIP (FLoating Instrument Platform).

Link:
Midlife refit of Scripps' Research Vessel Roger Revelle completed - Research vessel (R/V) Roger Revelle is back at work after a midlife refit...

By Venkatachari JagannathanChennai, Dec 31 : The year 2020 was a challenging year for the Indian atomic sector due to the Covid-19 pandemic. However, it still performed remarkably well attaining a major milestone and also taking steps towards setting up of a medical research reactor in public-private-partnership (PPP) mode, a top sector official said.

A significant milestone achieved during the year was the achievement of first criticality of KAPP-3 (Kakrapar Atomic Power Project-3), the first of a kind indigenous 700 MW Pressurised Heavy Water Reactor (PHWR), which is the first in a series of 16 such reactors being set up in the country, Atomic Energy Commission (AEC) Chairman K.N. Vyas told IANS.

The KAPP-3 attained first criticality (controlled self-sustaining nuclear fission chain reaction) in July despite the handicap of the Covid-19 lockdown.

All efforts are being made to start commercial operation of the first 700 MW unit at Kakrapar, KAPP-3 by March 2021. Work on the KAPP-4 and RAPP 7&8 (Rajasthan Atomic Power Project) is being expedited. In KAPP-4 and RAPP-7, main plant civil construction and erection of major equipment has been completed and balance activities are in progress. In RAPP-8, various construction and erection activities are in progress, Vyas said.

According to him, the nuclear power stations operated at the highest standards of safety and generated 40,718 Million Units of electricity in 11 months of this year (January to November 2020).

Continuing with the trend of setting records in long continuous operation by Indian nuclear power reactors, NAPS-2 (Narora Atomic Power Station-2) continued to operate during the year, registering 851 days of continuous operation as on December 23, 2020, Vyas added.

The year also saw Union Finance Minister Nirmala Sitharaman announcing setting up of a research reactor for production of medical isotopes in PPP mode to offer affordable treatment for cancer and other diseases.

Soon after that the Department of Atomic Energy (DAE) set the process rolling and in November, appointed the Strategic Consultant and Transaction Advisor for setting up research reactor under PPP.

The consultant is engaged from initial feasibility study to executing the concession agreement, Vyas said.

According to him, the proposed reactor is designed to maximise irradiation capacity, and thus a large quantity of variety of radioisotopes shall be produced in the reactor.

Majority of the isotopes are for medical use. In addition, some of the isotopes would also have industrial use. As per internal assessment, it is expected that with this research reactor, it will be possible to meet the complete requirement of medical isotopes in the country, Vyas said.

In addition, there will be considerable scope to export of radioisotopes. It is planned to have processing facility complex along with the reactor. It would be worlds largest (production volume wise) radio-isotopes production and processing facility, he added.

Following the appointment of the consultant, the Bhabha Atomic Research Centre (BARC) held discussions with the consultant to finalise the business case and PPP model.

To know the expectation of the industry and probable investors, A.T. Kearney has initiated dialogues with leading players/investors of the different field, Vyas said.

As regards the reactor design, the design detailing is under progress.

With several more atomic power plants planned needing fuel, attempts are being made by Uranium Corporation of India Ltd (UCIL) to increase production.

Looking forward to 2021, Vyas said, the plan is to commence commercial operation of KAPP-3 (700 MW) while work on KAPP-4 (700 MW), RAPP-7&8 (2700 MW), Kudankulam Nuclear Power Project-3&4 (21,000 MW) and Gorakhpur Haryana Anu Vidyut Pariyojana (GHAVP-2700 MW) projects are planned to be speeded up in the year after the slowdown in 2020 due to the pandemic.

In addition, start of construction of KNPP 5&6 (2X1000 MW) at Tamil Nadus Kudankulam is also planned in the year.

The year also saw transfer of 25 different technologies through 38 Transfer of Technology (ToT) agreements. The nuclear technologies transferred were developed under various fields like agriculture, bioscience, environment, medical equipment, advanced instrumentation, engineering, water, radiation and chemical.

Vyas said BARC is engaged in research and development activities related nuclear agriculture and food preservation technologies like radiation induced mutants with superior traits, development of super absorbent hydrogel for dry regions and shelf-life extension of fruits.

One Trombay crop variety TKR Kolam (Trombay Karjat Kolam) has been released and gazette notified for commercial cultivation by Ministry of Agriculture & Farmers Welfare. Two rice varieties, Vikram-TCR and CG Trombay Jawaphool were released by State Variety Release Committee (SVRC), Chhattisgarh. Breeder seed production of Trombay crop varieties was carried for groundnut (332 quintals), rice (15 quintals) and pulses (20 quintals), Vyas said.

Pointing out that drought is the most severe stress that hinders the growth of crop plants, causing substantial yield loss to farmers, Vyas said: BARC has developed a super-absorbent polymeric hydrogel using radiation technology. The hydrogel can soak up about 400 times its own weight and act as a water reservoir in the soil, releasing the stored water upon plant/root demand.

In arid areas, the use of BARC hydrogel can increase the water holding capacity of soil, which significantly improves the plant health and productivity. The hydrogel has shown potential during testing in BARC and the same is being tested with the help of State Agriculture Universities, he added.

While BARC will continue to develop and test new mutants/breeding lines of oilseed, pulses and cereals, it will also take up development of technologies for shelf life extension of fish, spreads, vegan milk made of chick pea and preservation of agriculture produce (wheat, pointed gourd etc.), Vyas remarked.

Other notable developments are the biokit for detection of group of organophosphate (OP) and organocarbamate (OC) pesticides for qualitative detection of presence of pesticides in food commodities such as vegetables and fruits and 1,000 Litre Per Hour (LPH) reverse osmosis technology based water treatment plants were commissioned at villages of Maharashtra and West Bengal in alignment with the Jal Shakti Abhiyan and Jal Jeevan Mission of the Centre, Vyas said.

(Venkatachari Jagannathan can be contacted at v.jagannathan@ians.in)

Disclaimer: This story is auto-generated from IANS service.

Excerpt from:
2020: A year of challenge and achievement for Indian nuclear sector - The Siasat Daily

DUBLIN, Jan. 4, 2021 /PRNewswire/ -- The "Biopreservation Market by Type, Application, End-user, and Geography - Global Forecast to 2026" report has been added to ResearchAndMarkets.com's offering.

Biopreservation is a process that assists in the conservation of biospecimens such as DNA, saliva, and plasma. This process of biopreservation generally increases the durability, shelf life, and purity of the biosamples. The types of equipment in this process include freezers, liquid nitrogen, consumables, and also media & laboratory information management systems.

This process is also used to preserve food and extend its shelf life, specifically by using lactic acid bacteria. Growth in healthcare spending is assumed for better access to quality healthcare and advanced technology products such as biopreservation facilities, thereby widening the growth expectations. Moreover, the bio-banks, hospitals, and gene banks, which are major end-users for this market, are stimulating the key providers to establish technologically advanced biopreservation products to improve patient outcomes. The Biopreservation Market is projected to grow at a rate of 9.2% CAGR by 2026.

The biopreservation market has been analyzed by utilizing the optimum combination of secondary sources and in-house methodology, along with an irreplaceable blend of primary insights. The real-time assessment of the market is an integral part of our market sizing and forecasting methodology. Our industry experts and panel of primary participants have helped in compiling relevant aspects with realistic parametric estimations for a comprehensive study. The participation share of different categories of primary participants is given below:

In the market for biopreservation, the application of biopreservation consists of therapeutic applications, research applications, clinical trials, and other applications. The biopreservation is primarily applied in therapeutics due to the advancements in regenerative medicine & customized medicine, an increase in the shift of cord blood banking, and the rising incidence of chronic diseases.

The end-users of the biopreservation market include biobanks, gene banks, hospitals, and other end users. The biobanks segment is expected to have a major share in the market. The major share of this segment is attributed to the increasing preference for the preservation of stem cells and the rising numbers of sperm and egg banks.

Further, according to the regional market of biopreservation, the North American region is recorded for the colossal share in the market. This is due to the continuous drug developments and the arrival of advanced therapies in the domain of biomedical research. Additionally, the increasing requirement of expensive and improved treatment for patients' chronic diseases is the key factor.

The rising incidence of chronic diseases, including cardiac, renal diseases, diabetes, and obesity, is the crucial factor that will propel the biopreservation market growth in the prevailing period. Government initiatives to encourage stem cell therapies to treat the disease, which will again propel market growth. Conversely, the strict regulations for producing biopreservation products and the evolution of room temperature storage procedures may limit the biopreservation market growth.

Merck KGaA, Avantor, Inc., Bio-Techne Corporation, BioLife Solutions, Inc., Thermo Fisher Scientific Inc, ThermoGenesis Holdings, Inc., Worthington Industries, Inc., Chart Industries, Inc, So-Low Environmental Equipment Co., Inc., Princeton BioCision, LLC, Shanghai Genext Medical Technology Co. Ltd, Exact Sciences Corporation, Helmer Scientific, Inc., CryoTech, Inc., Arctiko, Nippon Genetics Europe, PHC Holdings Corporation, STEMCELL Technologies, Inc., AMS Biotechnology, and OPS Diagnostics. These are the few companies list of the biopreservation market.

Since the rapid increase in the number of research and developments gives the way of potentials for market growth, the biopreservation of biological samples has become a crucial segment. This helps the researchers to access the data of the number of people by the preserved biological samples.

This research presents a thorough analysis of market share, the present trends, and forthcoming evaluations to explain the approaching investment pockets.

This research provides market insights from 2020 to 2026, which is predicted to allow the shareholders to capitalize on the forthcoming opportunities.

This report further offers comprehensive insights into the region, which helps to understand the geographical market and assist in strategic business planning and ascertain future opportunities.

Key Topics Covered:

1. Executive Summary

2. Industry Outlook2.1. Industry Overview2.2. Industry Trends

3. Market Snapshot3.1. Market Definition3.2. Market Outlook3.2.1. PEST Analysis3.2.2. Porter Five Forces3.3. Related Markets

4. Market characteristics4.1. Market Evolution4.2. Market Trends and Impact4.3. Advantages/Disadvantages of Market4.4. Regulatory Impact4.5. Market Offerings4.6. Market Segmentation4.7. Market Dynamics4.7.1. Drivers4.7.2. Restraints4.7.3. Opportunities4.8. DRO - Impact Analysis

5. Type: Market Size & Analysis5.1. Overview5.2. Biopreservation Media5.2.1. Nutrient Media5.2.2. Sera5.2.3. Growth Factors & Supplements5.3. Biospecimen Equipment5.3.1. Temperature Control Systems5.4. Freezers5.5. Cryogenic Storage Systems5.6. Thawing Equipment5.7. Refrigerators5.7.1. Accessories5.7.2. Alarms & Monitoring systems5.7.3. Incubators5.7.4. Centrifuges5.7.5. Other Equipment

6. Application: Market Size & Analysis6.1. Overview6.2. Therapeutic Applications6.3. Research Applications6.4. Clinical Trials6.5. Other Applications

7. End User: Market Size & Analysis7.1. Overview7.2. Biobanks7.3. Gene Banks7.4. Hospitals7.5. Other End Users

8. Geography: Market Size & Analysis8.1. Overview8.2. North America8.3. Europe8.4. Asia Pacific8.5. Rest of the World

9. Competitive Landscape9.1. Competitor Comparison Analysis9.2. Market Developments9.2.1. Mergers and Acquisitions, Legal, Awards, Partnerships9.2.2. Product Launches and execution

10. Vendor Profiles10.1. Merck KGaA10.1.1. Overview10.1.2. Financials10.1.3. Products & Services10.1.4. Recent Developments10.1.5. Business Strategy10.2. Avantor, Inc10.2.1. Overview10.2.2. Financials10.2.3. Products & Services10.2.4. Recent Developments10.2.5. Business Strategy10.3. Bio-Techne Corporation10.3.1. Overview10.3.2. Financials10.3.3. Products & Services10.3.4. Recent Developments10.3.5. Business Strategy10.4. BioLife Solutions, Inc10.4.1. Overview10.4.2. Financials10.4.3. Products & Services10.4.4. Recent Developments10.4.5. Business Strategy10.5. Thermo Fisher Scientific Inc10.5.1. Overview10.5.2. Financials10.5.3. Products & Services10.5.4. Recent Developments10.5.5. Business Strategy10.6. ThermoGenesis Holdings, Inc10.6.1. Overview10.6.2. Financials10.6.3. Products & Services10.6.4. Recent Developments10.6.5. Business Strategy10.7. Worthington Industries, Inc10.7.1. Overview10.7.2. Financials10.7.3. Products & Services10.7.4. Recent Developments10.7.5. Business Strategy10.8. Chart Industries, Inc10.8.1. Overview10.8.2. Financials10.8.3. Products & Services10.8.4. Recent Developments10.8.5. Business Strategy10.9. So-Low Environmental Equipment Co.,Inc10.9.1. Overview10.9.2. Financials10.9.3. Products & Services10.9.4. Recent Developments10.9.5. Business Strategy10.10. Princeton BioCision, LLC10.10.1. Overview10.10.2. Financials10.10.3. Products & Services10.10.4. Recent Developments10.10.5. Business Strategy

11. Companies to Watch11.1. Shanghai Genext Medical Technology Co. Ltd11.1.1. Overview11.1.2. Products & Services11.1.3. Business Strategy11.2. Exact Sciences Corporation11.2.1. Overview11.2.2. Products & Services11.2.3. Business Strategy11.3. Helmer Scientific, Inc11.3.1. Overview11.3.2. Products & Services11.3.3. Business Strategy11.4. CryoTech, Inc11.4.1. Overview11.4.2. Products & Services11.4.3. Business Strategy11.5. Arctiko11.5.1. Overview11.5.2. Products & Services11.5.3. Business Strategy11.6. Nippon Genetics Europe11.6.1. Overview11.6.2. Products & Services11.6.3. Business Strategy11.7. PHC Holdings Corporation11.7.1. Overview11.7.2. Products & Services11.7.3. Business Strategy11.8. STEMCELL Technologies, Inc11.8.1. Overview11.8.2. Products & Services11.8.3. Business Strategy11.9. AMS Biotechnology11.9.1. Overview11.9.2. Products & Services11.9.3. Business Strategy11.10. OPS Diagnostics11.10.1. Overview11.10.2. Products & Services11.10.3. Business Strategy

12. Analyst Opinion

13. Annexure13.1. Report Scope13.2. Market Definitions13.3. Research Methodology13.3.1. Data Collation and In-house Estimation13.3.2. Market Triangulation13.3.3. Forecasting13.4. Report Assumptions13.5. Declarations13.6. Stakeholders13.7. Abbreviations

For more information about this report visit https://www.researchandmarkets.com/r/711zgr

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Worldwide Industry for Biopreservation to 2026 - Key Drivers, Restraints and Opportunities - Yahoo Finance

If you've ever wondered why we get goosebumps, you're in good company -- so did Charles Darwin, who mused about them in his writings on evolution. Goosebumps might protect animals with thick fur from the cold, but we humans don't seem to benefit from the reaction much -- so why has it been preserved during evolution all this time?

In a new study, Harvard University scientists have discovered the reason: the cell types that cause goosebumps are also important for regulating the stem cells that regenerate the hair follicle and hair. Underneath the skin, the muscle that contracts to create goosebumps is necessary to bridge the sympathetic nerve's connection to hair follicle stem cells. The sympathetic nerve reacts to cold by contracting the muscle and causing goosebumps in the short term, and by driving hair follicle stem cell activation and new hair growth over the long term.

Published in the journalCell, these findings in mice give researchers a better understanding of how different cell types interact to link stem cell activity with changes in the outside environment.

"We have always been interested in understanding how stem cell behaviors are regulated by external stimuli. The skin is a fascinating system: it has multiple stem cells surrounded by diverse cell types, and is located at the interface between our body and the outside world. Therefore, its stem cells could potentially respond to a diverse array of stimuli -- from the niche, the whole body, or even the outside environment," said Ya-Chieh Hsu, the Alvin and Esta Star Associate Professor of Stem Cell and Regenerative Biology, who led the study in collaboration with Professor Sung-Jan Lin of National Taiwan University. "In this study, we identify an interesting dual-component niche that not only regulates the stem cells under steady state, but also modulates stem cell behaviors according to temperature changes outside."

A system for regulating hair growth

Many organs are made of three types of tissue: epithelium, mesenchyme, and nerve. In the skin, these three lineages are organized in a special arrangement. The sympathetic nerve, part of our nervous system that controls body homeostasis and our responses to external stimuli, connects with a tiny smooth muscle in the mesenchyme. This smooth muscle in turn connects to hair follicle stem cells, a type of epithelial stem cell critical for regenerating the hair follicle as well as repairing wounds.

The connection between the sympathetic nerve and the muscle has been well known, since they are the cellular basis behind goosebumps: the cold triggers sympathetic neurons to send a nerve signal, and the muscle reacts by contracting and causing the hair to stand on end. However, when examining the skin under extremely high resolution using electron microscopy, the researchers found that the sympathetic nerve not only associated with the muscle, but also formed a direct connection to the hair follicle stem cells. In fact, the nerve fibers wrapped around the hair follicle stem cells like a ribbon.

"We could really see at an ultrastructure level how the nerve and the stem cell interact. Neurons tend to regulate excitable cells, like other neurons or muscle with synapses. But we were surprised to find that they form similar synapse-like structures with an epithelial stem cell, which is not a very typical target for neurons," Hsu said.

Next, the researchers confirmed that the nerve indeed targeted the stem cells. The sympathetic nervous system is normally activated at a constant low level to maintain body homeostasis, and the researchers found that this low level of nerve activity maintained the stem cells in a poised state ready for regeneration. Under prolonged cold, the nerve was activated at a much higher level and more neurotransmitters were released, causing the stem cells to activate quickly, regenerate the hair follicle, and grow new hair.

The researchers also investigated what maintained the nerve connections to the hair follicle stem cells. When they removed the muscle connected to the hair follicle, the sympathetic nerve retracted and the nerve connection to the hair follicle stem cells was lost, showing that the muscle was a necessary structural support to bridge the sympathetic nerve to the hair follicle.

How the system develops

In addition to studying the hair follicle in its fully formed state, the researchers investigated how the system initially develops -- how the muscle and nerve reach the hair follicle in the first place.

"We discovered that the signal comes from the developing hair follicle itself. It secretes a protein that regulates the formation of the smooth muscle, which then attracts the sympathetic nerve. Then in the adult, the interaction turns around, with the nerve and muscle together regulating the hair follicle stem cells to regenerate the new hair follicle. It's closing the whole circle -- the developing hair follicle is establishing its own niche," said Yulia Shwartz, a postdoctoral fellow in the Hsu lab. She was a co-first author of the study, along with Meryem Gonzalez-Celeiro, a graduate student in the Hsu Lab, and Chih-Lung Chen, a postdoctoral fellow in the Lin lab.

Responding to the environment

With these experiments, the researchers identified a two-component system that regulates hair follicle stem cells. The nerve is the signaling component that activates the stem cells through neurotransmitters, while the muscle is the structural component that allows the nerve fibers to directly connect with hair follicle stem cells.

"You can regulate hair follicle stem cells in so many different ways, and they are wonderful models to study tissue regeneration," Shwartz said. "This particular reaction is helpful for coupling tissue regeneration with changes in the outside world, such as temperature. It's a two-layer response: goosebumps are a quick way to provide some sort of relief in the short term. But when the cold lasts, this becomes a nice mechanism for the stem cells to know it's maybe time to regenerate new hair coat."

In the future, the researchers will further explore how the external environment might influence the stem cells in the skin, both under homeostasis and in repair situations such as wound healing.

"We live in a constantly changing environment. Since the skin is always in contact with the outside world, it gives us a chance to study what mechanisms stem cells in our body use to integrate tissue production with changing demands, which is essential for organisms to thrive in this dynamic world," Hsu said.

Read the rest here:
The real reason behind goosebumps - Jill Lopez

More than 25 years ago, it was a patient with a port-wine stain who inspired Alster to learn more about the then-fledgling world of lasers. Alster accepted a fellowship in Boston, where her patient traveled to receive treatments. So in essence, I changed her life because I significantly lightened the birthmark to the point where she didn't need to cover it, says Alster. And she changed my life because I wouldn't have looked into lasers if it wasn't for her... I ended up opening up my own center in Washington, D.C. in 1990. And at that time it was the only freestanding laser center in the world.

Lasers and Scars

Lasers can treat many types of scars, including surgical scars, acne scars, and scars from injuries. They penetrate the epidermis to stimulate new, healthy skin cell growth. The most common lasers used in scar removal are ablative fractional carbon dioxide lasers, Nd:YAG, nonablative fractional lasers, and pulsed dye lasers.

Lasers and Hair Removal

Laser hair removal is a medical procedure that uses a concentrated beam of light to remove unwanted hair. The laser emits a light that is absorbed by the pigment (melanin) in the hair. The light energy is converted to heat, which then damages the hair follicles that produce hairs. This damage inhibits or delays future hair growth. With repeated treatments, laser hair removal can permanently reduce unwanted hair. While all hairs dont fall out immediately, they will shed within days to weeks of treatment.

But lasers arent only used for hair reduction. Low-Level Laser Therapy (LLLT) is a relatively new treatment that uses low-power lasers to stimulate hair growth. Its hypothesized that LLLT stimulates stem cells in the hair follicle and shifts the follicles in the anagen (growth) stage of the hair cycle.

How is LED different from lasers?

Commonly confused with lasers, light-emitting diodes (LED) can reduce fine lines, increase collagen production, and smooth skin by using varying color wavelengths of visible LED light. Lasers, on the other hand, often use a single wavelength, and the beam is ideal for stimulating changes that only respond to very specific wavelengths (hair removal, dark spot removal, etc.).

Can you combine lasers with other in-office treatments in the same session?

Short answer: Yes! Depending on the laser you and your dermatologist choose, you can get filler or Botox in the same treatment. Some experts will specifically recommend injectables with Fraxel within the same appointment since its considered safe and delivers a rather dramatic final result. Alster often combines non-ablative laser treatments with microneedling to amplify the effects.

Can you be too young for lasers?

When deciding whether or not to try a laser, your age shouldnt be a major deciding factor. It's more of a matter of the problem you want to fix, not how old you are. Many young people have rosacea, acne, sun spots, and sun damage all of which are treatable with lasers. Still, less-intensive therapies, such as chemical peels, are likely enough to repair young, relatively healthy skin (and are often less expensive).

Is it safe to laser your skin at home?

There are various options for at-home laser treatments that you can use safely. Typically, at-home devices have significantly lower power than those used in a medical setting, in order to reduce risks. Many lasers for wrinkles or acne are simply LED light products, like the Dr. Dennis Gross Skincare DRx SpectraLite mask. There are, however, a few at-home non-ablative fractional lasers available, like the Tria SmoothBeauty Laser.

Michelles Current Favorites

While everyones skin is different and your personal dermatologist knows whats best for you Michelle says she slathered her face with Aquaphor following a Fraxel treatment. You really do need to keep your skin moist [afterward], she says. And then it's all about sunscreen, sunscreen, sunscreen. Right now, Michelle is into Dr. Loretta Urban Antioxidant Sunscreen SPF 40, which has a slight tint.

Jennys Current Favorites

Like Michelle, Jenny used Aquaphor after getting Fraxel. She also used CeraVe Moisturizing Cream post-treatment to help speed up healing. And in order to cover up the sandpaper-like texture and small, dark dots that often arise after getting Fraxel, Jenny used Oxygenetix Oxygenating Foundation. A lot of dermatologists and plastic surgeons recommend it for people to use this when they're healing, she says. It's thicker than what I would normally use for foundation, but it gave a really seamless finish [and] got me through that week or two after [treatment].

Like many in-office treatments, lasers often come with some downtime. But good things come to those who wait: Lasers can have a huge impact on the look and health of your skin.

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The Complete Guide to Laser Treatments for Hair and Skin | The Science of Beauty Podcast | Allure - Allure

What happened

CRISPR gene-editing stocks are being hit hard by a broader biotech sell-off on Tuesday. Shares of CRISPR Therapeutics (NASDAQ:CRSP) were down 9.1% as of 12:05 p.m. EST. Editas Medicine (NASDAQ:EDIT) stock had declined 13.7%, while Intellia Therapeutics (NASDAQ:NTLA) shares had slumped 11.4%.

There wasn't a clear reason behind today's rout of biotech stocks. The biggest negative story in the biopharmaceutical industry centered on Arcturus Therapeutics' disappointing early-stage results for its single-dose COVID-19 vaccine candidate.

Image source: Getty Images.

CRISPR Therapeutics, Editas, and Intellia tend to be more volatile than most stocks. None of the companies have products on the market yet. Their valuations are based solely on investors' optimism about their future prospects. When that optimism wanes, the stocks sink.

It's important to keep in mind, though, that nothing has actually changed about the prospects for any of these three gene-editing biotechs. In many ways, those prospects are as strong as they've ever been.

CRISPR Therapeutics and its big partner, Vertex Pharmaceuticals, reported encouraging new data earlier this month for experimental gene-editing therapy CTX001 in treating rare genetic blood disorders beta-thalassemia and sickle cell disease. Editas also announced positive preclinical data for its candidate targeting the same diseases a few weeks ago and filed for U.S. regulatory clearance to begin a phase 1 clinical study in treating sickle cell disease. Intellia presented promising preclinical data in early December for its experimental gene-editing therapies targeting acute myeloid leukemia (AML) and rare genetic disease alpha-1 antitrypsin deficiency.

Each of these stocks is falling today based on no news directly related to their businesses or pipelines. That creates a buying opportunity for investors who remain confident about each company's direction.

What really matters for these three biotechs is the clinical progress for their respective pipeline candidates. And key developments are on the way for all three companies.

CRISPR Therapeutics expects to report additional data from early-stage studies of immuno-oncology candidates CTX110, CTX120, and CTX130 in 2021. Editas hopes to begin a phase 1 study evaluating EDIT-301 in treating sickle cell disease and continue patient enrollment in a phase 1 study of EDIT-101 in treating eye disease Leber congenital amaurosis type 10 (LCA10) in the new year. Intellia anticipates submitting for regulatory clearance to begin early-stage studies of NTLA-5001 in treating AML and for NTLA-2002 in treating hereditary angioedema next year.

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Why CRISPR Therapeutics, Editas Medicine, and Intellia Therapeutics Stocks Are Sinking Today - The Motley Fool