Archive for January, 2021

The Telegraph

Schools could open before Easter, Gavin Williamson has suggested, saying he will give a two-week warning to headteachers. The Education Secretary said he "would certainly hope" that children would be back in the classroom by early April, adding that he wants this to happen at the "earliest possible opportunity". It is the first time Mr Williamson has hinted at a possible timeline for the reopening of schools, and comes after Dr Jenny Harries, the deputy chief medical officer, suggested schools in some parts of the country will reopen sooner than those in others. Primary and secondary schools were ordered to close at the start of the month to all but the children of key workers and the most vulnerable youngsters. Announcing the latest national lockdown on January 4, Boris Johnson said schools would need to remain shut until the February half-term at the earliest. On Thursday, Mr Williamson said a key factor in determining when schools could reopen would be whether pressures on the NHS had eased sufficiently. He told BBC Radio 4's Today programme that headteachers will be given "absolutely proper notice" about when they need to prepare to reopen, adding that a "clear two-week notice period" will be factored in so schools have time to prepare for pupils' return. "Schools were the last to close, schools will be the first to open," the Education Secretary said. "I want to see that as soon as the scientific and health advice is there to open at the earliest possible stage, and I would certainly hope that that would be before Easter. "Any decision to reopen schools to all children as all decisions in terms of schools will be based on the best health advice and the best scientific advice."

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One Killed as Motorcyclists Ride in Wrong Direction on San Francisco's Bay Bridge - Yahoo News UK

DILLON Dylan Pope concurs that 2020 was, by and large, not a great year. But he still found a way to make the most of it.

"It was a pretty tough year but having this to look forward to and reflect on has been something pretty big for me," he said.

Pope, a Montana Western defensive back, made the decision to donate bone marrow in December.

"I was nervous, but I was excited to help somebody," Pope said.

At the encouragement of his sister, Mariah, Pope registered with a non-profit called Be The Match in March, shortly after coronavirus knocked the world off kilter.

According to the organization's website, only one out of every 430 registered members will actually go on to donate bone marrow. Pope's sister has been registered for years without a match.

So, Pope was understandably taken aback when, after a little more than three months, he received a call telling him that he had been deemed a suitable donor for an anonymous recipient to receive his blood stem cells, which are derived from bone marrow.

"At first I thought it was fake," Pope said. "I didn't think there was any way it was going to happen after just three months."

With a donation date set in December -- because of confidentiality policies, Pope can't disclose what state or hospital the procedure took place at -- the next months were what one would expect: a lot of paperwork and a lot of blood tests.

The week before the donation, he began receiving daily injections to increase his stem cell count. He then made the trip with his younger brother, Brayton.

The process took eight hours and required only local anesthesia. A needle in his right arm drew blood, ran it through a machine that extracted stem cells and then a needle in his left arm injected blood back into his body.

"It's really not nearly as scary when you get there as you think it's going to be," Pope said.

It'll be a year before Pope learns the identity of who received his bone marrow. He's certain it'll be a moving, powerful experience.

"I bet it'll be pretty emotional thing for both of us, because it was pretty cool to be able to help them," Pope said.

Ryan Nourse, Montana Western's head football coach, said he wasn't surprised by Pope's willingness to donate bone marrow and said he and the program supported him the entire way.

"I think that's a really brave thing, courageous thing for Dylan to go do," Nourse said. "I think that selflessness will shine through to the other guys knowing that maybe I could help somebody in a similar position someday."

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'I was excited to help somebody': Montana Western's Dylan Pope reflects on donating bone marrow - MontanaSports

Mesoblast, MESO, is an Australian based biopharmaceutical company that has been a market favorite, even though the companys ups and downs have confused many investors.

The MESO share price has been inconsistent lately. This has prompted many investors to ask why. Analyzed carefully, MESO has done better than many stem cell businesses. Most stem cell businesses fail to ever make a profit and fail to even get a product to market. This can cause long-term problems with the stock price of any company.

ByMichael A. Mannen, MS

Mesoblast as a company is committed to offering groundbreaking cellular therapies for the treatment of many severe diseases using Mesenchymal Stem Cells. They are dedicated to cellular medicines and leveraging their stem cell technology. There are not many successful companies in this niche.

Adult stem cells are undifferentiated cells that divide and rebuild the damaged tissue. Mesenchymal Stem Cells are a type of adult stem cells generated from some of the adult tissues present in the body.

Stem cells have been found by scientists to have two properties: self-renewal and the potential to divide into specialized cell types. Multi-potent, mesenchymal stem cells are found to be present in many adult tissues. The bone marrow is considered by many scientists to be the most usable reservoir of adult human stem cells.

For several disorders, such as heart failure, the capacity to rebuild tissue may be groundbreaking for treatment. And this has been the inspiration for many companies exploring stem cell therapies.

However, what differentiates Mesoblast from other stem cell companies is its approach to treating inflammatory diseases. Their products have the potential to make breakthroughs a reality for many diseases.

The company has developed and manufactured its own patented mesenchymal lineage cells to be used for a range of ailments. These have a potential for the regeneration of tissues. These cells, however, secrete a number of biomolecules which can help the body heal more than just tissue damage. They may be important to supporting immune responses needed for recovery in many diseases.

Possible rejection of the patients immune system is the biggest problem with the use of stem cell therapies in heart diseases and other diseases. This can worsen many illnesses.

MESO does appear committed to the quality of its product. For MESO it is a question of the effectiveness and safety of their products. Its a long and winding road to provide adequate scientific proof when presenting breakthrough treatments to regulators. Many less reputable organizations have touted stem cells without doing the necessary scientific investigation or seeking the necessary regulatory approval. Mesoblast is trying to do things the right way. Committing to doing science the right way leads to a lot of inevitable ups and downs. This raises financial speculation and can lead to wild fluctuations in the stock price of any company.

A further significant advantage of some of Mesoblasts products is that they apparently can be administered to patients without needing donor matching. This increases their viability. Moreover, it allows for a wide spectrum of patients to be treated from their products. This gives them an advantage in comparison with other firms and should potentially allow them to increasingly gain a larger market share.

Of great interest to investors include the many clinical trial phase 3 products that Mesoblast has in its pipeline. These include MPC-06-ID, Remestemcel-L, and REVASCOR.

Remestemcel-L is a Mesoblast therapy that may theoretically have properties to help with the treatment of ventilator-dependent patients with COVID-19 patients. However, a clinical trial reported some concerns with the therapy meeting its primary endpoint. And it sent the stock down in December 2020. Obviously, there is a large demand for the treatment of complications linked to Covid-19, so this bad news disappointed investors.

However, another therapy has shown promise in the DREAM-HF Phase 3 for patients with chronic heart failure. Although the Revasacor did not stop heart failure, it did seem to deliver dramatic reductions in heart attacks and other negative cardiovascular events that plague heart failure patients.

Heart failure is a pathology that involves ones heart having trouble pumping. The condition impacts millions of people worldwide. In order to feed and maintain it working, the heart muscle depends on a continuous supply of oxygen rich blood. Having stem cell therapies is highly desirable to treat cardiovascular diseases. Hopefully, many Cardiovascular disorders can be treated with stem cell therapies in the future.

Other conditions such as hypertension and Coronary artery disease can help lead to heart failure. According to the Mayo Clinic, heart failure can cause significant health complications and lead to Liver and Kidney damage in patients.

Some scientists believe that Mesenchymal Stem Cells when used to treat cardiovascular diseases can preserve the myocardium by reducing the intensity of inflammation and supporting angiogenesis. Angiogenesis is a mechanism used by the body to create new blood vessels. Their low immunogenicity once more makes them a perfect treatment. This helps ensure that the immune system of the patient does not produce a negative response to the therapy. This theoretically can give stem cell therapies an advantage over some protein-based treatments that are easily recognized by the patients immune system.

This product could be a major development for Mesoblast moving forward, although further analysis and testing is still needed.

Stem cell therapies are not without experimental and medical challenges. For example, there are concerns with the ability of stem cell migration to tissues that require regeneration. There may also be cases whereby stem cells are divided into unintended cells. There may also be difficulties with the manufacturing and culturing of stem cells. Identification of Mesenchymal stem cells in cell populations can be problematic. From a scientific point of view, bone marrow derived Mesenchymal Stem Cells are known to be the best source for obtaining these cells in the human body.

Mesoblast has a wide range of advanced research programs related to different stem cell therapies. MPC-06-ID could potentially be a viable therapy for treating chronic low back pain attributable to degenerative disc disease.

These are products that consumers should be thrilled about.

The company has solid financials for a stem cell company and has a lot of cash on hand. The stock had a market cap of over 2 billion on 9/30/2020 and a 52-week high of 21.28. Lately the news surrounding the companys clinical trials has been a potpourri of both good and bad, so the share price has settled at around $9. It has a float of 93.7 million shares.

Mesoblast is a really exciting healthcare business. The business has made a commitment for the future. And it should be a stock that investors continue to follow.

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Mesoblast Limited: Is Stemcell Therapy Ready For Prime Time? - Sick Economics

Introduction

Chronic myeloid leukemia (CML) is a hematological malignancy that develops when the 9;22 translocation in a single hematopoietic stem cell (HSC) results in the expression of BCR-ABL1 tyrosine kinase fusion protein. If left untreated, CML progresses over approximately 5 years, from relatively benign chronic phase to accelerated phase, and then to fatal blast crisis. The introduction of tyrosine kinase inhibitors (TKIs) specifically targeting the BCR-ABL1 fusion protein was a breakthrough in the management of CML, leading to a significant reduction in mortality and improved 5-year survival rates. However, despite the high annual acquisition costs of all the TKIs; first-, second-, and-third line TKIs1 induce only transient responses in the 10% to 15% of CML patients diagnosed in advanced phase, suboptimal responses in approximately 30% of CML patients during chronic phase (CP) cases that experience disease progression each year during, and only 1020% chance of successful treatment discontinuation due to disease persistence.2 Among the causes of disease persistence, studies have shown that CML leukemia stem cells (LSC) play a major role in inducing therapeutic resistance and disease progression because they are able to self-renew.3,4 These LSC a rare subset of immature cells residing in the bone marrow niche are protected from the action of TKI5 because these cells are normally quiescent and the TKIs are designed to target malignant blast cells that proliferate. That is why current strategies are not able to effectively eliminate the LSC or the disease.3 In CML, LSC are primitive cells expressing CD34+ CD38- with the 9;22 translocations, or the Philadelphia chromosome (Ph).6 However, these markers cannot distinguish the cancer hematopoietic cells from normal ones. Additionally, the BCR-ABL fusion gene encodes for an intracellular tyrosine kinase protein rather than a surface protein, calling for the need to identify unique surface biomarkers for efficient targeting of this cell population with subsequent eradication of the root of the disease.

In 2010, a single biomarker, Interleukin 1 receptor accessory protein (IL1RAP), was found to be up-regulated on the cell surface of BCR-ABL+ LSC. They were able to distinguish Ph+ from Ph- LSCs using IL1RAP.7 A polyclonal anti-human IL1RAP was generated that not only targeted the LSC population but also killed normal peripheral blood mononuclear cells, indicating that this marker was not specific to the LSC.7 Another characteristic cell surface marker has been investigated; ThomsenFriedenreich antigen (TF, or CD176) a tumor-associated carbohydrate epitope. The CD176 antigen was found to be expressed on the surface of various cancer-initiating cells, such as breast carcinomas,8 colorectal carcinomas,9 several leukemias,10 and other types of cancer, but was absent from almost all normal adult cell types.11 CD176 was also found to be expressed on the surface of CD34+ hematopoietic stem cells of the K562 erythroblastic leukemia cell line; a cell line derived from a CML patient. Being strongly expressed on the surface of cancer cells and virtually absent from normal tissues, CD176 was evaluated as a suitable target for cancer biotherapy8 with the development of an anti-CD176 antibody that induced apoptosis of leukemic cells.12

Using monoclonal antibodies (mAb) as a tool for cancer therapy still has its limitations. Patients who receive mAb therapy may develop drug resistance or fail to respond to treatment owing to the multiple signaling pathways involved in the pathogenesis of cancer and other diseases.13 Targeting more than one molecule has proven to circumvent the regulation of parallel pathways and avoid resistance to the treatment.14 Bi-specific antibodies (Bis-Ab) are antibodies that can recognize two different epitopes. They can redirect specific immune cells to the tumor cells to enhance tumor eradication, enable the simultaneous blocking of two different targets that have common signaling pathways, or interact with two different cell-surface antigens instead of one with subsequent boosting of the binding specificity.13 Thus, the identification of two surface markers specific to the cancer stem cells would be useful in characterizing and targeting CML stem cells, without affecting other blood cells.

In this study, we evaluated co-expression of IL1RAP, linked to BCR-ABL+ expression, and the CD176 antigen, carried on the hematopoietic stem cell marker CD34 molecule, in CML patients. We identified PBMCs co-expressing CD34, IL1RAP, and CD176 antigens using flow cytometry, a finding that allowed for subsequent separation and targeting of such cells from normal HSCs. A bi-specific antibody (TF/RAP), was generated in order to target the IL1RAP+ and CD176+ cell population among PBMCs in patients with CML. We used a flow-cytometry assay as a cell-based assay to measure the antibody binding capability of the TF/RAP Bis-Ab to the cell surface antigens. Our TF/RAP Bis-Ab, increased targeting of the IL1RAP+ and CD176+ cell population among CML PBMCs but not corresponding normal cells, using complement-dependent cytotoxicity assay (CDC). This novel TF/RAP Bis-Ab may provide a novel strategy for the eradication of CML stem cells.

Deidentified samples of peripheral blood from healthy volunteers were obtained from Gulf Coast Regional Blood Bank (Houston, TX, USA) after signing informed consent and used as reference samples. Deidentified samples of peripheral blood mononuclear cells (PBMCs) from consented patients with CML were obtained from Oncology Research Gundersen BioBank (https://www.gundersenhealth.org/research/biobank/, La Crosse, WI, USA). While the samples were de-identified, necessary CML patient characteristics were collected (Table 1). The collection and dissemination protocols for the samples are approved by The Gundersen Human Subjects Committee/Institutional Review Board (IRB) and are in full compliance with National Cancer Institute Best Practices for Biospecimen Resources. Because the de-identified samples were received through Biobanks and not through direct intervention/interaction with a research subject, the Tulane University Human Research Protection Office was notified and this study was classified by the IRB as exempt as the study did not meet the definition of human subjects research according to US Federal policy (HHS regulations, 45 CFR part 46, subpart A, also known as the Common Rule). The study was conducted in accordance with the Declaration of Helsinki.

Table 1 CML Patients Characteristics

HEK 293FT cell line (Invitrogen # R70007) was cultured in DMEM (Life Technologies, Carlsbad, CA, USA) supplemented with 10% heat-inactivated fetal bovine serum (FBS), 100 U/mL penicillin, 100 g/mL streptomycin sulfate, and 4.0 mM L-glutamine (Gibco BRL products, Gaithersburg, MD), at 37C in a humidified 5% CO2 incubator. The KG1 cell line (ATCC #CCL-246) and transduced derivative cells were cultured in Iscoves Modified Dulbeccos Medium (Life technologies) supplemented with 20% FBS at 37C in a humidified 5% CO2 incubator. K562 cell line (ATCC# CCL-243) was maintained in RPMI-1640 (Life technologies) supplemented with 10% FBS, 100 U/mL penicillin, 100 g/mL streptomycin sulfate at 37C in a humidified 5% CO2 incubator.

The IL1RAP cDNA was PCR amplified from an expression plasmid containing Human IL-1RAcP/IL-1R3 Gene ORF cDNA (Sino biological Inc., HG10121-CM) using Clone Amp HiFi PCR Premix (Takara Bio USA, Inc.), and primers that included either a BamHI or an XhoI site (F-IL1RAP: acgggatccccaccaagcttggtaccatgac; R-IL1RAP: acgctcgagttatacatttttcaaagatg). The PCR fragment was gel extracted as above, sub-cloned into BamHI and XhoI sites in the pHRST-MPSV vector according to standard protocols and confirmed by restriction mapping and sequencing.

Transient production of lentiviral particles in adherent HEK293T was modified from previously described.15 Briefly, HEK293T cells were seeded in a T-75 flask, where we used 4.0 g of envelope plasmid pMPSV-VSV-G, 10.0 g packaging plasmid psPAX2, and 26 g transfer plasmid that has the gene of interest. In our case, the transfer plasmid is either the antibody plasmid or the control. The plasmids were mixed into 500 L 0.25 M CaCl2 (Sigma Aldrich, St. Louis, MO) and incubated at room temperature for 5 minutes, and then mixed with 500 L 2xHBS and briefly vortexed. The mixed transfection cocktail was then incubated for 3 minutes at room temperature, and added into the medium of the cells, and mixed gently to make an even distribution. After 16 hours of incubation, the medium was replaced with fresh medium and collected every 24 hours for 3 days. The conditioned medium that contained the vector virus was then pelleted for 10 minutes at 1500 g and passed through a 0.45-m filter to remove the cell debris, and then frozen at 80C for long-term storage, or used for the transduction of target cells.

Lentiviral transduction was done as previously described.1618 In brief, lentiviral supernatant was added to KG1 cells cultured in complete IMEM. After overnight incubation, the lentiviral vector was removed, and fresh media was added. After 48 hours, IL1RAP expression was demonstrated by flow cytometry using anti-Human IL-1 RAcP/IL-1 R3 PE-conjugated antibody (#FAB676P, R&D Systems, Minneapolis, MN).

The CH and CL constant domains in the pLM219 plasmids were amplified with 0.5 nM overlapping mutant primers (Table S1), Deep Vent Polymerase (New England Biolabs), and reaction buffer for forty cycles at 94C for 10 seconds, 60C for 45 seconds, and 72C for 2 minutes. Initial fragments were purified, combined, and used to amplify the entire heavy or light domains (Table S2). The mutated fragments were then gel purified and sub-cloned into their corresponding vectors using restriction enzymes according to standard protocols (Table S2). Sequences were then verified by restriction digestion and sequencing.

For antibody sequences towards CD176 (TF) and IL1RAP, the VH and VL domains from two clones with the most conserved amino acid sequences (TF Clone 1 and Clone 2 called TF1 and TF2 for CD176; Clone 4B6 and Clone 4G9 called RAPa and RAPb for IL1RAP, respectively) were chosen from published sequences.20,21 IL1RAP antibody was designed to target the extracellular membrane anchor-proximal region that comprises an amino acid primary sequence VPAPRYTVELAC within 10 to 15 amino acids of amino acid 361 of human ILR1AP (Gene bank accession Q9NPH3) while the TF antibody was designed to target the same Gal(13)GalNAc disaccharide epitope20 as the Bis-Ab. Variable domains (VD) were codon-optimized and synthesized (Gene Art, Invitrogen) to be compatible with 15 base pairs of homologous sequences on both the 3 and 5 ends of pLM2 recipient plasmid flanking the EcoRI restriction enzyme site.

The pLM2 expression vector was digested with EcoRI to generate a double-stranded break. An In-Fusion HD cloning kit (Clontech, Inc) was used to clone the VD regions of the antibodies between the leader and constant regions of the pLM2 vectors. The correct clones were identified by PCR and restriction mapping and then verified by sequencing.

Adherent HEK cells were transfected as above. A total of 14 g high-quality plasmid-DNA, 10% GFP plasmid for assessment of transfection efficiency, while the rest was heavy and light chain plasmid DNA combined at a ratio of 1:1. Six to 8 hours later, cells were gently washed once with PBS and fresh growth medium added. Sixteen hours post-transfection, the medium was replaced with DMEM supplemented with 5% FCS and incubated at 5% CO2 for 24 hours prior to the initial collection of antibody supernatant. A second collection was made after a further 24 hours.

Flow antibodies used were as follows: anti-TF/CD176 mAb mouse IgM (Glycotope, Berlin, Germany) targeting Gal1-3GalNAc epitope; FITC-conjugated anti-mouse IgM secondary antibody (-chain specific, #F9259; Sigma); PE-conjugated mouse anti-human IL-1 RAcP/IL-1 R3 monoclonal IgG1 antibody, epitope Ser21-Glu359 (#FAB676P, R&D Systems); APC-conjugated mouse anti-human CD34 monoclonal IgG1 antibody (#QBEnd10, FAB7227A-025, R&D Systems); APC-conjugated mouse antihuman IgG monoclonal antibody (Clone G18-145, mouse IgG1 , #550,931, BD Pharmingen).

LIVE/DEAD Fixable Aqua Dead Cell Stain Kit (#L34957, Invitrogen); Vibrio Cholera Neuraminidase (VCN; Sigma Aldrich Inc), an enzyme used to expose the CD176 on the surface of expressing cells. Flow cytometric analyses were performed in a BD LSR Fortessa (BD Biosciences, USA) and flow cytometric cell sorting was done in a FACSAriaII (P0010) cell sorter (BD Biosciences, USA). The amount of bi-specific antibody bound to the receptors was calculated from the frequency of total IgG bound receptors.

Sorted cells were received in RPMI media and then fixed using the standard 3:1 methanol: acetic acid fixative. Standard procedures were used for FISH hybridization and washing.22 The BCR/ABL1 Plus translocation, dual fusion probe set (Cytocell Inc., Tarrytown, NY) was used. Slides were analyzed using Leica Biosystems Cyto Vision. FISH nomenclature was described according to the ISCN 2016.23

CD34+CD176+IL1RAP+ and CD34+CD176+IL1RAP- cells were sorted from PBMC samples derived from patients with CML. Cells (1 x 103) were plated in Metho Cult Express (#04437, Stem Cell Technologies, Vancouver, Canada) semi-solid media containing recombinant human IL-3, IL-6, G-CSF, GM-CSF, SCF, TPO and cultured for 2 weeks in a humidified atmosphere at 37C with 5% CO2. Fourteen days after plating, the number of colonies was counted by microscopy.24,25

The capacity to induce CDC was assessed essentially as has been described.2628 Briefly, target cells (1105 cells) were pre-incubated at 37C for 60 min with diluted antibodies. Human serum from human male AB (Sigma Aldrich) (20% v/v) was added to the cells as a source of complement and incubated at 37C for an additional 45 min. Cells were then put on ice and viability was determined by staining with LIVE/DEAD staining and detected using a FORTESSA flow cytometer (BD Biosciences). CDC activity was expressed as a percentage of lyses as determined from the increase in the percentage of cells stained positive with the LIVE/DEAD marker compared to the control samples. Cycloviolacin O2 (CyO2, 0.05nM), a pore-forming peptide, was used as a positive control because it kills cells with the similar mechanisms as CDC by causing pores in the cell membrane.

The capacity to induce CDC was assessed essentially as has been described.2628 Briefly, target cells (1105 cells) were pre-incubated at 37C for 60 min with diluted antibodies. Human serum from human male AB (Sigma Aldrich) (20% (v/v)) was added to the cells as a source of complement and incubated at 37C for an additional 45 min. Cells were then put on ice and viability was determined by staining with LIVE/DEAD staining and detected using a FORTESSA flow cytometer (BD Biosciences). CDC activity was expressed as a percentage of lyses as determined from the increase in the percentage of cells stained positive with the LIVE/DEAD marker compared to the control samples. Cycloviolacin O2 (CyO2, 0.05nM), a pore-forming peptide, was used as a positive control because it kills cells with the similar mechanisms as CDC by causing pores in the cell membrane.

We measured the production of the Bis-Ab by ELISA. Plates were initially coated with goat anti-Human IgG heavy chain antibody (Axell) and blocked with PBS containing 0.5% Tween 20 (Fisher), 10% FBS (FetalPlex Animal Serum Complex, GeminiBio, Cat#100-602), 4% whey protein (BiPRO, AGROPUR). Undiluted or diluted supernatant was added, including the standard curve samples (human IgG MAb 1.7B, kindly provided by Dr. James Robinson), and negative blocking buffer. After incubating at 37C for 60 min, the plates were washed. Then, goat anti-Human lambda antibody conjugated to HRP (Southern Biotech, Cat# 207005) was added at 1:300 in blocking buffer for 60 min and washed five times. A mixture of 0.1M Na Acetate (pH 6), peroxide, and TMB substrate were added. The reaction was terminated by adding 1M phosphoric acid, and the absorbance of each well was measured at 450 nm using a Synergy H1 microplate reader (BioTek).

For each experiment, more than three independent replicates were conducted, and the results were expressed as average standard deviation. Comparison of multiple groups was conducted using ANOVA-based Test and p< 0.05 (*) represented significances with statistical meaning. Calculation of the Kd was done using the equation % RO = [Ab]/([Ab]+Kd) 100%, where RO is the receptor occupancy, Ab is the concentration of antibody and Kd is the equilibrium dissociation constant.

In order to analyze the co-expression of CD176 and IL1RAP antigens on CD34+ cells, peripheral blood mononuclear cells from a normal volunteer (NPBMCs), patients with CML, and K562 cells were isolated and stained with anti-CD34, anti-CD176, and anti-IL1RAP monoclonal antibodies and analyzed by flow cytometry (Figure 1A). It has been previously established that these markers were not expressed on normal PBMCs nor on stem cells7,10 CD34+ cell expression ranged from an average 938% in CML samples versus 83.7% in K562 cells (Figure 1A, upper panel). Within the CD34+ cell population, CD176 and IL1RAP antigens were variably expressed in CML samples, ranging from 1.35% in CML-4 to over 50% in CML-1 (Figure 1A, lower panel), while CD176+ IL1RAP+ was detected in 78% of CD34 cells in K562 cells. Surprisingly, surface co-expression of CD176 and IL1RAP was not only detectable on CD34+ cells in patients with BCR-ABL positive CML but was also demonstrable in cells from a treated patient who was BCR-ABL negative (CML-2) (Figure 1B). In Figure 1C, CD34+ cells revealed higher frequency of CD176+ IL1RAP+ in CML group compared to control sample (17.5% versus 3.4%, p<0.001).

Figure 1 CD176 and IL1RAP antigens are co-expressed on CD34+ Leukemia stem cells. Peripheral blood mononuclear cells from patients with CML and healthy volunteers were isolated and stained for flow-cytometry analysis. (A) FACS Dot Blot showing expression of CD34 (top row) and co-expression of CD176 and IL1RAP antigens on the CD34+ cells (bottom row) in PBMCs from patients with CML compared to NPBMCs. (B) Bar graphs showing the BCR-ABL status relative to the percentage of IL1RAP and CD176 co-expression in the CD34+ subsets from patients with CML as compared to the normal control and the positive control (K562 cells). The BCR-ABL status is indicated below the sample. The error bars represent the variation in two independent experiments. (C) Average percentage of CD34+ and CD34+ CD176+ IL1RAP+ subsets in normal versus CML patients respectively. (D) Bar graphs showing the average count of colony-forming units (CFU) per 1000 CD34+CD176+IL1RAP- cells (open bar) or CD34+CD176+IL1RAP+ cells (solid bar) obtained from CML-2 and CML-4 samples. **p< 0.01, n.s represents that there is no significant difference between groups.

In order to analyze the progenitor activity of the various subpopulations, CML-2 and CML-4 were flow-sorted for CD34+CD176+IL1RAP+ and CD34+CD176+IL1RAP- then plated in media t support hematopoietic colony formation. The number of colonies, or colony-forming units (CFU), in CD34+CD176+IL1RAP+ pool represented 6% of the sorted cells with a significant difference between both populations, p<0.01 (Figure 1D and Figure S1).

To facilitate correct interaction of the VH and VL domains, site-directed mutagenesis was used to generate knob-in-hole mutations in the heavy and light chains of the constant domains (Figure 2A) via polymerase chain reaction overlap extension (Figures S2 and 3). Two PCR reactions were performed to generate two amplicons with the specific mutations included in the overlapping primers. The two fragments were then combined in a subsequent fusion reaction, in which the overlapping ends anneal, allowing the 3 overlap of each strand to serve as a primer for the 3 extension of the complementary strand. The resulting fusion product served as a template for amplification of the entire constant domain. In order to circumvent the light chain mismatching, an Orthogonal Fab interface was generated. In one Fab, complementary mutation was introduced and verified at the heavy chain constant domain (CH1_H172A_ F174G) and at the light chain constant domain (CL_L135Y_S176W), respectively (Figures S46). For the heavy chain heterodimerization, we used the Knob-in-Hole strategy, where we inserted the CH3 mutations (S354C and T366W) into different heavy chains (Figures S7 and 8). The VH and VL sequences were synthesized and cloned into the new pLM2-CH and -CL plasmids (Figure 2A) where CD176 was represented by TF1 (VH1 and VL1) and TF2 (VH2 and VL2) while IL1RAP was represented by Clone 4B6 (VHa and VLa) and Clone 4G9 (VHb and VLb). Then, we generated the four different bi-specific antibody mixtures (TF1RAPa, TF1RAPb, TF2RAPa, and TF2RAPb) to evaluate the most effective Bis-Ab (Figure 2B). The bispecific antibody was quantified by ELISA at 283 ng/mL. Since ELISA used the human IgG heavy chain antibody as the primary antibody and a goat anti-human lambda antibody conjugated to HRP as the secondary antibody, these data also confirm the correct association of the heavy and light chains and ensure that monomers are excluded.

Figure 2 The bi-specific antibody arms. (A) Schematic diagram of the bi-specific antibody showing the mutant arms and the antigen-binding domains. Thomsen-Freidenrich or CD176 domains (TF); IL1RAP domains (RAP); variable domain-heavy chain (VH); variable domain-light chain (VL); L135Y and S176W mutations (Y-W) in constant domain-light chain; H172A and F174G mutations in CH1 domain (A-G); S354C (C) or T366W (W) mutations in CH3. (B) Antibody mixtures generated by transient transfection of HEK 293T cells. TF1 and TF2 was paired with RAPa and RAPb to generate four Bis-Ab mixtures. The bispecific antibody concentration was 283 ng/mL as measured with ELISA. The correct association of the human IgG heavy chain and the lambda light chain was confirm and monomers were excluded by using anti-IgG primary antibodies and anti-light chain secondary antibodies.

KG1 cell line is an acute myeloid leukemia cell line that is known to be a positive control for CD176. For optimizing the staining protocol of CD176, KG1 cells were pre-treated with VCN to expose CD176 antigens for better staining (Figure S9). In order to test the binding capability and functional potential of our bi-specific antibody, we generated a dual-positive cell line for expressing both IL1RAP and CD176 through lentiviral transduction (Figure S10A and B). IL1RAP expression was increased by 1.5 folds in KG1/RAP cells as verified by flow cytometry (Figure S10C and D).

CD176 antigen is a glycosylated antigen; a protein antigen bound to GAL-NAC moiety which makes the antigen displayed on the cell surface yet not easy to isolate.21 For this reason, a flow-cytometry assay was used to evaluate both the binding capability and toxicity of our Bis-Ab using the gating strategy in Figure S11. KG1 and KG1/RAP cell lines were treated with the various Bis-Ab mixtures. Binding percentage was calculated from the percentage of IgG positive cells, where the secondary IgG antibody is bound to the primary Bis-Ab. The TF1RAPa Bis-Ab showed the highest binding in KG1/RAP cells (Figure 3A) as compared to other mixtures (p<0.001). In contrast, the TF1RAPb antibody revealed slightly reduced binding in KG1/RAP cells. On treating KG1/RAP cells with increasing amounts of TF1RAPa, more binding to the dual-positive KG1/RAP cells was observed (Figure 3B). To demonstrate the specificity of the Bis-Ab, we measured the competition with the CD176 and the IL1RAP monoclonal antibodies. Increasing concentrations of the Bis-Ab specifically inhibited the binding of both the IL1RAP and CD176 mAbs (Figure S12). Then, our KG1/RAP cells were treated with the Bis-Ab TF1RAPa and complement prior to staining with the LIVE/DEAD Fixable Aqua Dead Cell Stain Kit, in order to evaluate whether CDC could be achieved using IL1RAP and CD176 as targets. Flow cytometric analysis revealed a significant increase in dead cells in the Bis-Ab treated CD176/IL1RAP dual-positive KG1/RAP population as antibody binding also increased (Figure 3C), p<0.001.

Figure 3 Validation of TF-RAP Bi-specific antibody in KG1 cell line and CML samples. (A) MFI for binding of different Bis-Ab mixtures in KG1/RAP (p <0.001). (B) Binding (%) of the Bis-Ab in KG1/RAP cell lines. (C) Shows live/dead (LD) staining (%) in KG1/RAP cell lines after treatment with the Bis-Ab and complement. (D) MFI for binding of different Bis-Ab mixtures p <0.001 in CML cells. (E) Binding of the Bis-Ab (%) in PBMCs from patients with CML. The binding affinity (Kd) of our bispecific antibody was 21ng/mL, calculated using the % RO = [Ab]/([Ab]+Kd) 100%, where RO is the receptor occupancy, Ab is the concentration of antibody, and Kd is the equilibrium dissociation constant. This Bis-Ab platform used in this study had the correct molecular weight (95 KDa) and assembled properly (93%) as revealed by SDS-PAGE analysis.38 (F) Live/dead (L/D) staining (%) from patients with CML after treatment with the Bis-Ab and complement. The red square were L/D positive cells treated with CyO2; the percent of L/D staining in normal PBMCs is shown in blue. Each point represents the mean increase in L/D staining SEM with three to four replicates. Data from normal samples were low for all doses (data not shown).

Binding of TF1RAPa, TF2RAPa, and TF2RAPb was also tested in PBMCs from patients with CML. Again, TF1RAPa showed the highest binding relative to other mixtures (p<0.001) (Figure 3D) and with increasing doses (Figure 3E). Based on the CML binding curve, the binding affinity (Kd) of our bispecific antibody was 21 ng/mL. Other therapeutic antibodies, such as ofatumumab directed against CD20, have shown significant CDC against peripheral blood cells obtained from CML patients in chronic phases26 and B cells in CLL,29 respectively. Thus, the TF1RAPa cocktail was used to generate the doseresponse curve and to evaluate whether CDC could be achieved using both IL1RAP and CD176 as targets. The ability of the TF1RAPa cocktail was compared to human anti-IL1RAP and anti-CD176 monoclonal antibodies to induce cell death in PBMCs from patients with CML. PBMCs from CML1-4 were tested in CDC assays in parallel to cells from healthy control samples. In CML cells, the binding of TF1RAPa mediated CDC at higher levels than in normal peripheral blood mononuclear control cells, correlating with the expression level of IL1RAP and CD176, particularly at lower antibody concentrations (Figure 3F). More strikingly, among peripheral blood cells, TF1RAPa did not induce CDC of normal cells, whereas a clear dose-dependent CDC effect was observed in CML cells (Figure S13A and B). To address the selectivity of IL1RAP/CD176-targeting antibodies, we also validated the bispecific antibody cytotoxicity on the various subpopulations in peripheral blood. The dual-positive CD176+IL1RAP+ cell populations showed the highest CDC activity as compared to CD176+IL1RAP-, CD176-IL1RAP+, and CD176-IL1RAP- populations (Figure 4 and S13CF, S14).

Figure 4 Dose-response curve of TF1RAPa Bis-Ab on CDC in CML samples. A dose-response curve showing the selective killing potential of CD176+IL1RAP+ subpopulation by the TF1RAPa Bis-Ab as compared to other subpopulations in PBMCs from patients with CML. Each point represents the mean SEM of the four samples.

Targeting molecules involved in multiple pathways is proving to be one of the most reliable strategies for eradicating cancer stem cells. In this report, we present a novel bi-specific antibody, TF/RAP, capable of targeting ThomsenFriedenreich (TF, CD176) and IL1RAP antigens on CD34+ HSCs in CML and on cell lines. TF is a glycoprotein that has many domains and motifs (eg, LGALS3, Gal(1,3)GalNAc, LGalS3BP), many related to signaling pathways. It is a known marker for ongoing tumorigenesis and metastasis, as it is expressed on various cancer-initiating cells.8 Interestingly, CD34 and LGALS3 were found to be co-expressed in myeloid cells.30,31 LGALS3 and ABL1 are involved in regulating RUNX1 and the transcription of genes involved in differentiation of hematopoietic stem cells,32 especially myeloid cells33 (Figure S15) IL1RAP, on the other hand, is a member of the Toll-like receptor superfamily and is a well-known co-receptor of IL1R1.34 IL1RAP plays a role in mediating the effect of the pro-inflammatory cytokine IL-1 and is also involved in activating T cells and mast cells after mediating the signal of IL-1 cytokine.35 It has previously been characterized as a tightly related marker for BCR-ABL positive cells.7 Together, both TF and IL1RAP were related to apoptotic pathways; IL1RAP up-regulation was associated with decreased apoptosis in AML,36 and anti-CD176 antibody induced apoptosis of CD176-positive leukemic cells through multiple pathways.12 Although we did not find a direct link between IL1RAP, CD176 and leukemogenesis, previous studies have shown that each of them is separately expressed on CD34+ cells in leukemia cell lines8,10,12 and patients with CML7

Therefore, we conducted this pilot study, in order to assess the co-expression of IL1RAP and ThomsenFriedenreich (CD176) antigens on CD34+ HSCs in peripheral blood of patients with CML, using FACS gene expression analyses. Flow-drop FISH and CFU assays were used for the separation of CD34+CD176 BCR-ABL+ and BCR-ABL CML stem cells, based on IL1RAP expression.7 CFU numbers were significantly lower in CD34+CD176+IL1RAP- cells than in CD34+CD176+IL1RAP+ cells, obtained from CML-2 and CML-4 samples (Figure 1D), particularly CML-2 sample which was obtained from a patient in remission (BCR-ABL-). We found that the frequency of clonogenic hematopoietic progenitor cells was increased in the CD34+ CD176+IL1RAP+ cells in these samples. Testing the stem-cell characteristics of these two cell populations in immune-deficient mice would have been advantageous. Yet, the low numbers of sorted CML cells acquired from the CD34+CD176+ IL1RAP and IL1RAP+ cell subpopulations, alongwith the general low engrafting efficiency of chronic phase CML cells in these mice7 prevented us from successfully performing such experiments. Importantly, as IL1RAP expression was correlated with changes from chronic phase (CP) into accelerated phase (AP) and blast phase (BP)37, we also found that the level of IL1RAP/CD176 co-expressionwas increased, in our patient samples, as the disease progressed, independent of the treatment status(Table S3).

To target both TF and IL1RAP simultaneously, we developed a Bis-Ab specific for both antigens. Because antibodies are normally heterodimers of two heavy and two light chains, we modified the constant domains in the Bis-Ab to maximize the correct interactions of the four immunoglobulin chains within single cells. Here, we used the orthogonal Fab design; CH1_H172A_F174G and CL_L135Y_S176W38 to facilitate selective assembly of the Fab arms for correct dimerization of the antigen-binding domains.39 Therefore, we mutated CH1 and CL binding sites to restrict the assembly of the Fab with the correct VD pairs. The RAP VDs were cloned with the wild type Fab; and the TF VD was linked to the mutant orthogonal Fab design. Published data have shown that the component proteins of this Bis-Ab platform proper assembly were detected at 93% and the complex had a molecular weight of 95 KDa, as revealed by SDS-PAGE analysis.38 Additionally, the CH3 for each Fab was mutated with previously described knob-into-hole mutations40,41 to facilitate hetero-dimerization between the TF and the RAP heavy chains. In our study, we used ELISA to demonstrate that both the VD and Fc were properly paired. Here, because the primary antibody was anti-human VL and the secondary antibody was anti-human IgG, quantifying the Bis-Ab also demonstrated the VD-Fc interactions.

To efficiently validate the specific binding of our Bis-Ab, we generated a dual-positive cell line; KG1/RAP. KG1 cell line expresses CD176+, but IL1RAP is low or absent. Therefore, we induced IL1RAP expression in KG1 cells by lentiviral mediated-gene transfer, as previously usedin both immune42 and leukemic cells.43 In the competitive binding assay, increasing concentrations of the Bis-Ab blocked the binding of CD176 and IL1-RAP monoclonal antibodies to the KG1/RAP and KG1 parental cells, demonstrating the specific binding of the Bis-Ab. The level of CD176 expression in KG1 cell line was detected before and after VCN treatment. Increased staining of the KG1/RAP cells compared to the parental KG1 cells indicated that expression of the IL1RAP facilitates the interaction of the Bis-Ab with the target cell. This increased binding of the Bis-Ab to the KG1/RAP cells also increased their susceptibility to complement-dependent cytotoxicity (CDC). We also observed increased binding and increased CDC in the CD176+ IL1RAP+ population of the peripheralblood from patients with CML. As a pilot study and given that on average, 50% of the cells within the CD34+ subpopulation in the patients tested were dual positive for CD176 and IL1RAP antigens, in addition to the almost undetectable CDC in CD34+ cells in normal controls, our data strongly support the idea that the bi-specific antibody (TF/RAP) indeed induces CDC preferentially in CD176+ IL1RAP+ CML CD34+ cells. In generating a bi-specific antibody that targets CD176 and IL1RAP, we are unique in providing proof of concept that CML CD34+CD176+ IL1RAP+ cells can be targeted while preserving corresponding normal cells. The potential to target multiple antigens is supported by studies that demonstrated increased or synergistic CDC activity by non-cross blocking CD20 antibody combinations.44

Therapeutic antibodies are commonly administered intravenously, yet selectivity and specificity are a major concern for reduced toxicity. CD176/IL1RAP co-expression was not present in monocytes unlike the reported weak but present IL1RAP expression in monocytes.7 Both antigens were low or absent in most types of normal bone-marrow progenitor and mature cell types, suggesting that CD176/IL1RAP dual targeting antibodies are expected to show low toxicity on normal hematopoietic cells. Being strongly expressed on the surface of cancer cells and virtually absent from normal tissues, CD176 was evaluated as a potential target for cancer biotherapy with the development of anti-CD176 antibody that induced apoptosis of leukemic cells.8 Added to this, antibodies against IL1RAP were found to be capable of blocking IL-1 signaling as well as inhibiting tumor cells' growth in AML,34 CML,7 breast cancer,45 prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain/CNS cancer, cervical cancer, esophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer, and sarcomas46 especially in cancer stem cells, or (CSCs) and progenitor cells, which are responsible, directly or indirectly, for the development of a solid tumor.47 Thus, it may be thatour Bis-Ab will not only eradicate the CD176+IL1RAP+ drug-resistantCML stem cells but also may have universal therapeutic potential for preventing relapses in both solid and hematological cancers.Given that the mode of action in CDC is having the antibody direct the complement pathway to target cell killing, we suggest that this therapeutic strategy would be independent of known mechanisms of TKI resistance in CML. Thus, the concept of complement-mediated killing of IL1RAP/CD176 expressing cells may also have the potential to eradicate such cells in patients, either alone or in combination with current regimens, in order to increase their therapeutic effectiveness. And finally, expanded studies need to be performed in order to confirm the co-expression of both markers, especially in resistant and relapsed cancer patients as well as in patient-derived xenografts (PDX).

The experimental research was mostly supported by a fellowship to REE from the Egyptian Ministry of Higher Education, Cultural, and Missions Section (JS 3577). The lentiviral vectorHRST-cmvGFPand the packaging plasmids were akind gift from Richard C.Mulligan in the Harvard Gene Therapy Institute. The human IgG heavy and light chain constant genes were provided by JE Robinson (Tulane University). C Wu and SEB were supported by AI110158 and/or OD01104-51; EUA and SEB were supported by the Applied Stem Cell Laboratory.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. All authors have given approval of the final version of the article; and have agreed to be accountable for all aspects of the work.

The abstract of this paper was presented at the AACR annual Meeting 2019; March 29 April3, 2019; Atlanta, GA, as a poster presentation with interim findings. The posters abstract was published in Poster Abstracts in the AACR meeting proceedings and as a supplement in the AACR Cancer Research Journal [https://cancerres.aacrjournals.org/content/79/13_Supplement/1222A].

Raghda Eldesouki reports grants from Egyptian Ministry of Higher Education. Stephen EBraun reports grants from Egyptian Ministry of Education, Alliance for Cardiovascular Research, NIAID OD01104, and Braun/McGroarty Charitable Fund, during the conduct of the study. In addition, Dr Raghda Eldesouki, Dr Stephen Braun, Dr Fouad Badr and Dr Eman Abdel-Moemen Mohammedhave apatent, PCT/EG2019/000014, pending. The authors report no other conflicts of interest in this work.

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[Full text] Identification and Targeting of ThomsenFriedenreich and IL1RAP | OTT - Dove Medical Press

NEW YORK, Jan. 20, 2021 /PRNewswire/ --BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of adult stem cell therapies for neurodegenerative diseases, announced today the peer-reviewed publication of a preclinical study in the journal Stem Cell and Research Therapy. The study, entitled "MSC-NTF (NurOwn) exosomes: a novel therapeutic modality in the mouse LPS-induced ARDS model," evaluated the use of NurOwn (MSC-NTF cell) derived exosomes in a mouse model of acute respiratory distress syndrome (ARDS).

ARDS is a type of respiratory failure that is frequently associated with COVID-19 and mediated by dysregulated cytokine production. While there are currently no effective therapies to prevent or reverse ARDS, mesenchymal stem cell (MSC)-derived exosomes have been suggested as a potential novel treatment option due to their ability to penetrate deep into tissues and efficiently deliver immunomodulatory molecules.

Results from the recently published study showed that intratracheal administration of NurOwn derived exosomes led to a statistically significant reduction in lung disease severity score (p < 0.05; based on criteria set forth by the American Thoracic Society Documents: Matute-Bello et al., Am J Respir Cell Mol Biol 44;725-738, 2011) and improvements in several additional clinically relevant lipopolysaccharide (LPS)-induced ARDS markers such as lung function, fibrin presence, neutrophil accumulation, cytokine expression, and blood oxygenation levels. Notably, these improvements were significantly superior to those observed following administration of nave MSC-derived exosomes.

"These exciting preclinical data suggest that NurOwn derived exosomes have the potential to treat COVID-19-induced ARDS or other severe respiratory complications, and that they are more effective than exosomes isolated from nave MSCs at combatting the various symptoms of the syndrome," said Dr. Revital Aricha, Vice President of Research & Development at BrainStorm. "This publication in a highly regarded journal provides important validation for the scientific advances and significance of BrainStorm's preclinical research programs, including on our exosome-based technology platform."

Chaim Lebovits, Brainstorm's Chief Executive Officer added, "While our primary focus is on advancing NurOwn towards regulatory approval in ALS, we continue to evaluate the potential of our exosome-based platform to address unmet medical needs. The publication of these proof-of-concept data highlights this potential, and we are now actively assessing next steps to determine how to best generate value. We are also actively discussing with possible partners several development opportunities for the exosome technology."

About NurOwn

The NurOwn technology platform (autologous MSC-NTF cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells can effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwn technology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug status designation from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has completed a phase 3 pivotal trial in ALS (NCT03280056); this trial investigated the safety and efficacy of repeat-administration of autologous MSC-NTF cells and was supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). BrainStorm is in active discussions with the FDA to identify regulatory pathways that may support NurOwn's approval in ALS. BrainStorm is also conducting an FDA-approved phase 2 open-label multicenter trial in progressive multiple sclerosis (MS). The phase 2 study of autologous MSC-NTF cells in patients with progressive MS (NCT03799718) completed dosing inDecember 2020, and topline results are expected by the end of the first quarter 2021.

For more information, visit the company's website atwww.brainstorm-cell.com.

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Statements in this announcement other than historical data and information, including statements regarding future clinical trial enrollment and data, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may," "should," "would," "could," "will," "expect,""likely," "believe," "plan," "estimate," "predict," "potential," and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, regulatory approval of BrainStorm's NurOwn treatment candidate, the success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwn treatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture and commercialize the NurOwn treatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

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Introduction

Bone remodelling is a tightly coupled lifelong process, whereby old bone is removed by osteoclasts (bone resorption) and new bone is formed by osteoblasts (bone formation).1,2 Osteocytes, which act as mechanosensors/endocrine cells, and bone lining cells3 are also involved in bone remodelling.4 Myriad pathophysiological factors affecting bone remodelling have been observed in skeletal diseases such as osteoporosis, arthritis and periodontal disease.5 Oxidative stress is one of the pathophysiological factors affecting bone remodelling. Oxidative stress stimulates osteoclast differentiation, thereby enhancing bone resorption.6,7 Reactive oxygen species (ROS) stimulate the apoptosis of osteoblasts and osteocytes, thus affecting bone formation. ROS also activate mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinases (ERK1/2), c-Jun-N terminal kinase (JNK) and p38, and enhance osteoclastogenesis and bone resorption.811 These phenomena skew the bone remodelling process in favour of bone loss.

Antioxidants are compounds which reduce free radicals and oxidative stress.12 Antioxidants have been reported to promote differentiation of osteoblasts, bone formation and survival of osteocytes, as well as suppressing osteoclast differentiation and activity.8,1315 Some studies associate the age-related reduction in circulating antioxidants to osteoporosis in rats and women.1618 A decline in antioxidant levels has been reported to promote bone loss by triggering the tumour necrosis factor-alpha (TNF)-dependent signalling pathway,6 while administration of antioxidants, such as vitamin C, E, N-acetylcysteine and lipoic acid, have been reported to exert favourable effects in animal models of osteoporosis1921 and individuals with osteoporosis.2225

Caffeic acid (CA) is a metabolite of hydroxycinnamate and phenylpropanoid commonly synthesized by all plant species. It is a polyphenol present in many food sources like coffee, tea, wine, blueberries, apples, cider, honey and propolis.26 CA and its major derivatives including caffeic acid phenethyl ester (CAPE) and caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE) are reported to possess potential antibacterial, antidiabetic, antioxidant, anti-inflammatory, antineoplastic and cardioprotective activities (reviewed in2729). As a potent antioxidant, CA has been demonstrated to decrease lipoperoxyl radicals (ROO) by donating a hydrogen atom to its corresponding hydroperoxide, which terminates the lipid peroxidation chain reaction. It also inhibits human low-density lipoprotein (LDL) oxidation induced by cupric ions.30 Furthermore, it interacts with other compounds, such as -tocopherol, chlorogenic and caftaric acids, to exert more potent antioxidant activity in a variety of different systems.3133 Therefore, the antioxidant activities of CA might protect against the negative effects of oxidative stress on bone cells and the skeletal system. This systematic review aims to summarise the effects of CA and its derivatives on bone cells and bone in literature.

A systematic literature search was conducted from July until November 2020 using PubMed, Scopus, Cochrane Library and Web of Science databases to identify studies on the effects of caffeic acid on bone and bone cells including osteoblasts, osteoclasts and osteocytes. The search string used was (1) caffeic acid AND (2) (bone OR osteoporosis OR osteoblasts OR osteoclasts OR osteocytes).

Studies with the following characteristics were included: (1) original research article with the primary objective of determining the effects of caffeic acid on bone and bone cells; (2) studies using cellular or animal models, or humans; (3) studies administering caffeic acid as a single compound but not in a mixture or food. Articles were excluded if they (1) do not contain original data; (2) use food rich in caffeic acid or mixtures containing caffeic acid. The bibliography of relevant review articles was traced for potential articles missed during database search. The search results were organised using EndNoteTM software (Clarivate Analytics, Philadelphia, USA). Duplicates were identified using EndNoteTM and confirmed by manual checking.

Two authors (S.O.E. and K.L.P.) searched the same databases using the search string mentioned and screened the search results. All the articles that did not match the selection criteria were excluded. Next, the articles which used caffeic acid in treating models other than bone-related diseases were removed. Finally, articles which used caffeic acid in combination with other compounds were also excluded. Any disagreement on the inclusion or exclusion of articles was resolved through discussion among the two authors. The corresponding author (K.Y.C.) had the final decision on articles included if a consensus could not be reached between authors responsible for screening. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklist.34 Steps in the selection process, from identification, screening, eligibility to the inclusion of articles, are shown in Figure 1.

Figure 1 Flowchart of the article selection process.

From the literature search, 381 articles were identified, of which 87 were obtained from PubMed, 182 were from Scopus, 3 from Cochrane Library and 109 from Web of Science. A total of 155 duplicate articles were identified and removed. Of the 226 articles screened, 202 articles were excluded based on the selection criteria, whereby 51 articles did not contain primary data (3 book chapters, 2 commentary and 46 review articles), 147 articles and 2 conference abstracts presented topics irrelevant to the current review, a conference abstract had been published as a full-length research article and another conference abstract did not contain sufficient experiment details (Supplementary Material). Finally, 24 articles fulfilling all criteria mentioned were included in the review.

The included studies were published between 2006 and 2020. Seven studies were in vitro experiments using mouse bone marrow macrophages (BMMs), RAW264.7, RAW D and MG63 osteoblast cell lines3541 while 19 studies were in vivo studies using Sprague Dawley/Sprague Dawley albino rats, Wistar/Wistar albino rats, Balb/c mice, lipopolysaccharide (LPS)-resistant C3H/HEJ mice, C57BL/6J mice and ICR mice.35,38,4258 No human studies on this topic were reported.

Six in vitro studies focused on the effects of CA on osteoclast differentiation from haematopoietic cells using macrophage colony-stimulating factor (M-CSF), receptor activator of NF-B (RANK) ligand (RANKL) or TNF-,3539,41 while one in vitro study focused on the effect of CA on osteoblasts using MG63 osteoblast cell line.40 Four in vitro studies used CA doses between 0.15 M.35,37,38,40 Ang et al.36 used doses between 00.3 M and Sandra et al.41 and Sandra and Ketherin39 used a dose of 10 g/mL (55.5 M). The treatment period was 57 days for the differentiation of osteoclasts.

For animal studies, Duan et al.,55 Zawawi et al.,58 William et al.,51 Wu et al.,38 Zych et al.49 and Folwarczna et al.48,52 used CA or its derivatives at doses between 0.550 mg/kg via oral or intraperitoneal (i.p.) administration. Ucan et al.,57 Erdem et al.,53 Cicek et al.,54 Yigit et al.,45 Yildiz et al.50 and Tolba et al.56 used doses between 1020 mol/kg/day (2.845.69 mg/kg/day) via i.p. administration. Kizilda et al.4244 and Kazanciolu et al.46,47 used the dose of 10 mmol/kg/day (2.843 g/kg/day) for an i.p. administration, Kazanciolu et al.47 employed 50100 mmol/kg/day (14.2228.43 g/kg/day) for a localised administration, while Ha et al.35 used a collagen sponge soaked with CAPE with the final dose of 250 g/mouse. For oral administration, first-pass effect might affect the enteric absorption of CA or its derivatives.59 For i.p. administration, the injection is commonly performed at the lower left or right quadrant of the abdomen. The peritoneum can absorb the compounds fast and reach systemic circulation with greater bioavailability with fewer handling errors.60

The bone-related disease models used included ovariectomy (OVX)- or glucocorticoids (dexamethasone)-induced osteoporosis, polyethylene particle-induced bone defect and osteolysis, electromagnetic force (EMF)-stimulated bone loss, osteotomy- or anti-collagen antibody-induced arthritis (CAIA) and rapid maxillary expansion (RME) and LPS-induced periodontitis. The endpoints studied included bone microstructure, histomorphometry, bone remodelling and oxidative status. The effects of CA and its derivatives on bone remodelling have been summarized in Table 1.

Melguizo-Rodrguez et al. reported that 24-hour CA (1 M) incubation increased the number of MG63 osteoblast cells compared with control.40 Gene expression studies revealed that CA increased the expression of osteoblast-related genes such as bone morphogenetic protein-2 and -7 (BMP-2 and BMP-7), transforming growth factor-beta 1 (TGF-1), transforming growth factor-beta receptor 1, 2 and 3 (TGF-R1, TGF-R2 and TGF-R3) and osteoblastogenesis genes including Runt-related transcription (RUNX-2), alkaline phosphatase (ALP), collagen type 1 (COL-I), osterix (OSX) and osteocalcin (OSC).40 Additionally, pretreatment of CA (10 g/mL or 55.5 M) on RAW D cells for 2 h also significantly inhibited the RANKL and TNF-induced osteoclastogenesis with the suppression of p38 MAPK phosphorylation and tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells (OCLs) formation.39 Similarly, pretreatment of CA (0.1, 1 and 10 g/mL or 0.555, 5.55 and 55.5 M) on RAW D cells and BMMs for 3 days significantly inhibited the RANKL and TNF-induced osteoclastogenesis and NF-B activity in RAW-D cells and RANKL, TNF and M-CSF-induced osteoclastogenesis in BMMs.41

On the other hand, CAPE treatment (00.3 M; 57 days) suppressed the formation of TRAP-positive OCLs on RANKL-treated RAW264.7 cells and BMMs.36 Apoptosis occurred in CAPE-treated RAW264.7 cells with the disruption of the microtubule network in OCLs.36 Similarly, Kwon et al. reported that CAPE treatment (0.15 M) for 5 days suppressed OCLs formation from RANKL-stimulated RAW264.7 cells.37 Another study by Ha et al. treating M-CSF and RANKL-stimulated BMMs with CAPE (05 M for 57 days) also showed decreased OCLs formation in a concentration-dependent manner.35 The amount of TRAP-positive OCLs was decreased upon 0.1 and 0.5 M CAPE treatment by 30% and 95% respectively.35 No OCL formation was observed upon 1 M CAPE treatment.35 The anti-osteoclastogenic activities of CAPE are mainly contributed by its anti-inflammatory and antioxidant properties. Mechanistically, CAPE reduces superoxide anion generation by downregulating the nicotinamide adenine dinucleotide phosphate oxidase 1 (Nox1) expression through the interruption of nuclear factor-kappa B (NF-B) and c-Jun N-terminal kinase (JNK) signalling pathways.37 CAPE suppresses RANKL-mediated activation of the NF-B pathway by downregulating NF-B p65 subunit expression and its nuclear translocation,37 suppressing nuclear factor of activated T cells (NFAT) activities36 and degradation of NF-B inhibitor (IB),36,37 as well as inducing the degradation of IB kinase (IKK).37 CAPE also suppresses the expression and activation of JNK and its downstream transcription factors, such as c-Fos and c-Jun, which subsequently interrupt the protein activator-1 (AP-1) complex formation.37 Additionally, CAPE suppressed RANKL-induced activation of the Nox1 by inhibiting the Nox p47PHOX subunit translocation to the cell membrane and downregulation of Ras-related C3 botulinum toxin substrate 1 (Rac1) expression.37

On the other hand, Wu et al. reported that CADPE (0.15 M for 7 days) also concentration-dependently reduced OCL formation in the M-CSF and RANKL-stimulated BMMs and RAW264.7 cells.38 Mechanistic and characterisation examination revealed that CADPE suppressed RANKL-induced tumour necrosis factor receptor-associated factor 6 (TRAF6) activation and protein kinase B (PKB or also known as Akt) and activation of major MAPKs including ERK, JNK and p38.38 Subsequently, CADPE suppressed downstream expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), nuclear translocation of c-Fos protein and expression of osteoclastic markers, such as TRAP and cathepsin K, possibly through the non-receptor tyrosine kinase c-Src signalling.38 Interestingly, CADPE did not significantly affect the NF-kB signalling pathway and M-CSF-induced proliferation and differentiation of BMMs.

Supplementation of CA in animal models of bone loss yielded heterogeneous findings.48,49,52 This observation might be attributable to oral administration. Folwarczna et al. reported that CA (5 and 50 mg/kg, by stomach tube for 4 weeks) improved the bone mechanical properties by increasing the width of the trabecular metaphysis of the femur and decreasing the transverse growth in endosteal of the femur in OVX rats.48 Folwarczna et al. then demonstrated that CA (10 mg/kg/day; oral administration for 4 weeks) could reduce the width of tibial periosteal and endosteal osteoid compared with untreated OVX rats.52 However, CA did not promote or reduce the resorption of compact bone in the tibia of OVX-induced osteoporotic rats as evidenced by negligible changes of bone mass, bone mineral mass, bone mass/body mass ratio and bone mineral mass/body mass ratio.52 On the other hand, Zych et al. reported that CA at a similar dose (10 mg/kg/day; by stomach tube for 4 weeks) worsened the bone mechanical properties of healthy female Wistar Cmd:(WI)WU rats by decreasing the load of fracture at the femoral neck, decreasing the width of periosteal osteoid in the tibia and decreasing the width of the epiphysis and metaphysis trabecular in the femur compared with the negative control group.49

CAPE is the most extensively studied caffeic acid derivative in animal studies. The beneficial effects on new bone formation and healing upon systemic administration of CAPE had been reported.46,47,53,57 Erdem et al. reported that a low dose of CAPE (10 mol/kg; i.p. injection for 22 days) increased new bone formation and bone strength by increasing maximum torsional fracture momentum and degree of rigidity compared with negative control in rats that underwent unilateral femoral lengthening (osteotomy).53 Similarly, a 30-day i.p. injection of CAPE (10 mol/kg/day) also increased bone healing level in Sprague Dawley rats with cranial critical size bone defect.57 A higher dose of CAPE (10 mmol/kg/day, i.p. for 20 days) also further promoted the RME procedure-induced new bone formation in midpalatal suture of male Sprague Dawley rats.47 Similarly, a longer treatment period of CAPE (10 mmol/kg/day; i.p. injection for 28 days) also significantly promoted bone healing by increasing the total new bone areas in surgical-induced calvarial defects of male Wistar rats compared with the negative control.46 However, localised administration of CAPE (28 days) on surgical-induced calvarial defects by pre-mixing 50 and 100 mmol/kg CAPE solutions with gelatin sponges did not significantly improve the new bone formation.46

Localised and systemic administration of CAPE was reported to be beneficial in reducing osteolysis and bone loss.35,4245,50,5456,58 Ha et al. reported that collagen sponge implant impregnated with 250 g CAPE and RANKL could reduce osteoclastogenesis with significantly lesser TRAP-stained area in mouse calvariae compared with implants with RANKL only.35 Subcutaneous injection of CAPE (1 mg/kg/day for 10 days) reduced the polyethylene particle-induced calvarial osteolysis, surface bone resorption and TRAP-positive cells formation with an increase of bone volume (BV) on LPS-resistant C3H/HEJ female mice.58 However, no significant changes were observed in carboxy-terminal cross-linked type 1 collagen (CTX-1) and osteoclast-associated receptor levels among untreated and CAPE-treated rats with calvarial osteolysis.58

Similarly, Duan et al. reported that lower dose and frequency of CAPE injection (0.5 mg/kg twice a week; i.p. injection for 4 weeks) also increased the BV and trabecular number (Tb.N) due to the decrease of bone osteoclast formation (evidenced by decreased osteoclast number/bone perimeter) in OVX mice.55 Tolba et al. also reported that i.p. injection of CAPE (10 and 20 mol/kg) for 3 weeks increased femur weight and length in rats with dexamethasone-induced bone loss.56 The preservation of skeletal health in their study was associated with an improved antioxidant defence, such as higher levels of glutathione (GSH) and superoxide dismutase (SOD), and the reduction of malondialdehyde (MDA, lipid peroxidation product).56 This event led to an increase of osteoblastogenesis indicated by upregulation of RUNX-2 and ALP (osteoblast marker) levels56 On the other hand, decreased RANKL/osteoprotegerin (OPG) ratio was observed with CAPE treatment, indicating the suppression of osteoclastogenesis, which was further confirmed by lower acid phosphatase level and TRAP activity.56 In another study by Yildiz et al., CAPE (10 mol/kg/day; i.p. injection for 22 days) also increased the spine and femur BMD in rats with EMF-induced bone loss.50 Similarly, Cicek et al. reported a longer treatment of CAPE (10 mol/kg/day; i.p. injection for 28 days) also significantly improved the mechanical strength of cortical bone by increasing the breaking force, bending strength and total fracture energy in rats with EMF-induced bone loss compared with negative control.54

Additionally, a study by Wu et al. treated mice with an OVX-induced bone loss with a moderately high dose of CADPE (10 mg/kg; i.p. injection) every 2 days for 3 months.38 Results showed that CADPE could increase the BV fraction (BV/TV) and Tb.N, as well as decreased trabecular spacing (Tb.Sp) compared with the negative control.38 The improvement in the bone structure was contributed by reduced osteoclast number and eroded surface on the bone.38 Assessment of bone remodelling markers also revealed that serum TRAP5b and CTX-1 levels were reduced in CADPE-treated group compared with the negative control.38

On the other hand, CAPE was effective in reducing periodontitis-related bone loss and osteolysis.4245 CAPE (10 mol/kg/day, i.p. for 14 days) significantly reduced the subgingival ligature placement-induced periodontitis-mediated articular bone loss, histopathological features and severity of periodontal inflammation with lesser polymorphonuclear cells (PMNLs) infiltration in the junctional epithelium and connective tissues among Wistar albino rats.45 CAPE also suppressed the periodontitis-upregulated interleukin (IL)-1, IL-6, IL-10, TNF, MDA levels and the percentage of gingival apoptosis with the parallel restoration of periodontitis-downregulated GSH and glutathione peroxidase (GPx).45 Administration of high-dose CAPE (10 mmol/kg/day; i.p. for 15 days) in streptozotocin (STZ)-induced diabetic male Sprague Dawley rats reduced RANKL-positive osteoclast number, IL-1 levels, oxidative stress index (OSI), alveolar bone loss and histological analysis score in LPS-induced periodontitis. The treated rats also suffered lesser inflammatory reactions, ulcers and hyperemia.42 Similar changes of osteoclast number, IL-1 and OSI were observed in male Sprague Dawley rats with chronic stress and LPS-induced periodontitis treated with CAPE (10 mmol/kg/day, i.p. for 14 days).44 In addition, CAPE also increased the mesial and distal periodontal bone supports (MPBS and DPBS) in these rats.44 The effects of CAPE were sustained with a longer treatment period of CAPE (10 mmol/kg/day, i.p. for 28 days) on male Sprague Dawley rats with LPS-induced periodontitis.43

In contrast to the above findings, Williams et al. reported that subcutaneous injection of CAPE (1 mg/kg; at day 3, 7 and 10) did not reduce paw inflammation or bone loss in CAIA mice.51 Cartilage and bone degradation, as well as TRAP-positive cells on the bone surface and soft tissues, were still apparent in the supplemented CAIA group compared with the normal control.51

This systematic review found that although CA and its derivatives is a potential anti-osteoporosis agent by suppressing the formation of osteoclasts and their bone resorption activity, it worsened bone mechanical properties in some cases. The anti-osteoclastogenesis action of CA and its derivatives was mediated by the antioxidant activities, which blocked RANKL-induced TRAF6/Akt and MAPK signalling, as well as M-CSF/c-Src signalling. In animals, CA and its derivatives (mainly CAPE) prevented bone resorption in rodent calvariae when implanted in situ, facilitated the healing of bone defects, preserved bone structure and improved mechanical strength in osteoporosis models induced by OVX, dexamethasone, osteotomy, LPS-mediated periodontitis and EMF. However, CA did not alter bone resorption in OVX-induced osteoporotic rats and worsened the mechanical properties in normal rats. Additionally, CAPE did not suppress bone loss in rats with CAIA-induced bone loss.

Osteoblasts are bone-forming cells derived from bone marrow mesenchymal stem cells and are responsible for the synthesis, secretion and mineralisation of bone matrix.61 The expression of osteoblast markers was increased following CA or CAPE supplementation, an indication that CA and CAPE stimulated osteoblast proliferation, differentiation and maturation.40,56 Osteoblasts and osteocytes regulate the formation of osteoclasts through RANKL/OPG axis. Osteoblasts and osteocytes synthesise RANKL, which binds to RANK to activate the canonical pathway for osteoclastogenesis. They also secrete OPG, which is a decoy receptor for RANKL to suppress osteoclastogenesis. The production of RANKL is stimulated under conditions such as oestrogen deficiency62 and oxidative stress.63 Osteoclastogenesis can also be stimulated via a non-canonical pathway, for instance, through the binding of TNF with TNF receptor I or II.64 Glucocorticoids are potential modulators of RANKL/OPG axis, whereby dexamethasone is shown to downregulate OPG levels in osteoblasts.65 Tolba et al. showed that the RANKL/OPG level reduced in rats induced with dexamethasone with CAPE treatment.56 Other cellular studies showed that CA and its derivatives suppressed RANKL- and TNF-induced formation of OCLs from haematopoietic cells,3539 indicating that CA and its derivatives suppressed both canonical and non-canonical osteoclastogenesis.

The complex formed by the binding of RANKL to RANK causes the recruitment of the adaptor molecules tumour necrosis factor receptor-associated factors (TRAFs), including TRAF6.66 This event leads to the activation of several downstream signalling pathways, including c-Src/Akt/phosphatidylinositol 3-kinase and MAPKs (ERK/p38/JNK). CADPE was shown to suppress RANKL-induced activation of TRAF6 activation and the subsequent signalling pathways in multiple osteoclast progenitors, such as BMMs,38 RAW264.738 and RAW D cells.39 Sandra and Ketherin suggested that the downregulation of p38 is the key step of CA-mediated osteoclastogenesis.39 Upon activation, p38 initiates osteoclastogenesis by inducing NF-B and NFATc1 expression.67,68 Inhibition of p38 MAPK reduces RANKL (canonical) and TNF-induced (non-canonical) osteoclast formation.69

The NF-B pathway is another signalling pathway downstream of TRAFs critical for osteoclast differentiation and bone reabsorption activity. Upon activation, IKK (consisting of IKK, IKK and IKK) phosphorylates and degrades IB, which enables translocation of NF-B p65/p50 heterodimers into the nucleus to allow transcription of osteoclast-related genes.70 Kwon et al. demonstrated that the anti-osteoclastogenesis effects of CAPE were mediated via the degradation of total IKK, thereby preventing the phosphorylation and degradation of IB and subsequently suppresses the nuclear translation of p65.37 On the other hand, Wu et al. reported that CADPE did not affect phosphorylation or degradation of IB, as well as nuclear translocation, and DNA-binding activity of p65.38 This observation suggests that compared with CAPE, CADPE does not influence the NF-B signalling pathway.

ROS are one of the important secondary signals in the early stages of osteoclast differentiation.71,72 These ROS are mainly produced as superoxide anions by Nox1.73 Blocking of Nox1 ameliorates ROS production and the downstream MAPKs (JNK, p38 and ERK) and NF-B activation74 and subsequently suppresses the osteoclast formation.71 The reduction of Nox 1 and Rac1 expression by CAPE is accompanied by RANKL-downstream signalling, denoting that anti-osteoclastogenesis effects of CAPE are dependent on suppression of Nox1-mediated superoxide anion production. Besides, dexamethasone has been reported to increase the expression of oxidative stress-related genes in human osteoblasts.75 Tolba et al. showed that CAPE increased GSH and SOD but reduced MDA in the bone of the rats exposed to dexamethasone, indicating an improvement of redox status in the skeletal environment.56 Additionally, CAPE also reduced the OSI and bone loss with an improvement of bone support in rats with LPS-induced periodontitis.

NFATc1 is the master regulator of osteoclast-related gene expression, and it is activated by c-Fos and NF-B.76 Ha et al. observed that CAPE inhibited the recruitment of NF-B to NFATc1 promoter, and the combined effect of NF-B inhibition on c-Fos and NFATc1 may have caused CAPE to suppress osteoclastogenesis effectively.35 Holland et al. demonstrated a new fluorinated derivative of CAPE possesses potent anti-osteoclastogenic properties on RAW 264.7 cells by downregulating NFATc1 via suppression of c-Fos and NF-B signalling pathways.77 Besides, this new fluorinated CAPE also exhibits improved stability with a 2-fold higher potency than CAPE.77 On the other hand, although CADPE did not alter NF-B signalling, it still could suppress NFATc1 and other osteoclast-related markers, indicating other mechanisms of suppression could be involved, for instance, c-Src and MAPKs signalling pathways.38

Matrix metalloproteinases (MMPs), including gelatinases (MMP-2 and MMP-9) are examples of zinc-dependent extracellular matrix-degrading enzymes, which actively participate in bone resorption.78 MMPs are expressed as inactive proenzymes or zymogens that can be activated by several mediators including AP-1, NF-B, TNF and TGF.78 Currently, there is no study conducted to investigate the inhibitory effects of CA and CAPE on osteoclastic MMPs activity and its subsequent linkage in bone resorption; interestingly, CA and CAPE were reported to inhibit MMP-9 activity in human hepatocellular carcinoma HEP3B cells.79,80 This observation renders an interesting research gap in osteoclastic MMP inhibition upon CA and its derivatives treatment.

Suppression of osteoclastogenesis by CA or its derivatives have significant therapeutic potential against bone disorders induced by excessive bone resorption. Bone loss after osteotomy is a rapid process that affects both fractured and unfractured bone and may be incompletely reversible.81 CAPE was reported to improve bone formation and mechanical strength of bone in osteotomy.53 Exposure to EMF radiation caused by high-voltage transmission lines and transformers could affect bone health through decreased BMD, serum calcium and ALP level leading to the increase of bone resorption.82 CAPE increased the spine and femur BMD levels50 and increased mechanical strength of bones54 in rats exposed to EMF radiation. Total hip arthroplasty without cement often caused osteolysis induced by polyethylene particles.83 CAPE was shown by Zawawi et al. to prevent calvarial bone resorption in a murine polyethylene particle-induced osteolysis model.58 Therefore, biomaterials impregnated with CA or its derivatives could be adopted to prevent osteolysis in the arthroplasty procedure. CA has been incorporated in chitosan/(3-chloropropyl) trimethoxysilane scaffold for hard-tissue engineering applications and this adopted material exhibits antibacterial and anticancer effects.84 Ucan et al. observed that CAPE increased cranial bone healing in rats with critical size bone defect, suggesting that it could be administered systematically or locally to treat bone fracture/defect healing.57

Similarly, CAPE also effectively reduced the articular bone loss, inflammatory cytokines production and oxidative stress in rats with LPS-mediated periodontitis. Additionally, Wu et al.38 and Duan et al.55 demonstrated that CADPE prevented the ovariectomy-induced bone loss by suppressing osteoclast activity in a mouse model, while Folwarczna et al. showed increased width of trabecular metaphysis in the femur of OVX rats.48 Similarly, Tolba et al. showed improved bone formation and skeletal health in rats with dexamethasone-induced bone loss upon receiving CAPE.56 Additionally, CA and its derivatives may be involved in oestrogen production and signalling. Zych et al. reported that an oral administration of CA (10 mg/kg/day for 4 weeks) significantly restored the serum oestradiol levels in OVX rats.85 Interestingly, CA at 10 and 100 M did not cause any alteration in calcium content in the femoral-diaphyseal and metaphyseal ex vivo culture, suggesting its bone-protecting effect may not involve calcium metabolism and regulation.86 Additionally, CAPE was reported as a selective human oestrogen receptor agonist with the EC50 value of 3.72 M in oestrogen-responsive element transcription.87 A recent in silico study by Zhao et al. suggested potential osteoimmunological effects of CAPE, which may explain its biological activities on both immune and skeletal systems.88 However, the findings from this modelling study requires further validation through in vitro and in vivo models. As oestrogen deficiency due to menopause and glucocorticoids present the most significant cause of primary and secondary osteoporosis globally, CA and its derivatives have the potential to be used as an adjuvant therapy to existing osteoporosis management strategies. The mechanisms of action of CA and its derivatives in osteoclastogenesis have been summarized in Figure 2.

Figure 2 Mechanism of action of caffeic acid and its derivatives.

Abbreviations: , decrease or downregulate; ?, unknown mechanism; Akt, protein kinase B; AP-1, activator protein 1; CA, caffeic acid; CADPE; caffeic acid 3,4-dihydroxy-phenethyl ester; CAPE, caffeic acid phenethyl ester; c-Src, cellular sarcoma tyrosine kinase; ERK1/2, extracellular signal-regulated kinases 1/2; GM-CSF, granulocyte-macrophage colony-stimulating factor; Grb2, growth factor receptor-bound protein 2; IFN-, interferon-gamma; IL, interleukin; IL1R, interleukin-1 receptor; IB, NF-B inhibitor protein; IKK, IB kinase; LPS, lipopolysaccharide; M-CSF, macrophage colony-stimulating factor; M-CSF-R, M-CSF receptor; MAPKs, mitogen-activated protein kinases; NFAT, nuclear factor of activated T cells; NF-B, nuclear factor kappa B; NIK, MAPK kinase kinase 14; Nox1, nicotinamide adenine dinucleotide phosphate oxidase 1; OPG, osteoprotegerin; PI3k, phosphoinositide 3-kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; RANK, receptor activator of NF-B; RANKL, receptor activator of NF-B ligand; ROS, reactive oxygen species; TAK, MAPK kinase kinase 7; TLR4, Toll-like receptor 4; TNF, tumour necrosis factor-alpha; TNFR1/2, TNF receptor 1/2; TRAF2, tumour necrosis factor receptor-associated factor 2; TRAF6; tumour necrosis factor receptor-associated factor 6.

Regardless of the positive effects of CA on bone status, some studies have reported negative effects associated with supplementation of CA and its derivatives. CA supplementation did not affect the bone resorption52 and reduced transverse growth of endosteal in femur48 of rats with OVX-induced osteoporosis. In normal rats, CA supplementation even negatively affected their bone mechanical properties.49 Moreover, CAPE supplementation has been reported to stimulate the synthesis of PGE2,89 which mediates osteoclastogenesis through RANKL stimulation and activation of the NF-B pathway.90 This event will eventually increase TRAP-positive OCLs. Similarly, Williams et al. showed that CAPE did not suppress osteoclastogenesis in rats with CAIA.51

In term of safety, the International Agency for Cancer Research classifies CA as Class 2B (possibly carcinogenic to humans),91 and it was reported to induce renal tubular cell hyperplasia, forestomach hyperplasia, renal cell adenoma and forestomach cancer in rodents.9294 CA has been reported to be non-mutagenic and non-clastogenic.91 Therefore, its carcinogenicity may involve epigenetic modification. Human toxicity and carcinogenicity of CA and its derivatives remain unknown. CA also showed anti-implantation activity in pregnant mice at a median effective dose of 4.26 mg/kg/day.95 Similarly, 5 mg/kg/day and 150 mg/kg of CA in mice demonstrated anti-implantation activity in early pregnancy.96 On the other hand, 0.15 mg/kg/day, 5 mg/kg/day and 150 mg/kg/day of CA for 21 days in mice showed no maternal toxicity, foetal teratogenesis or post-natal effects on pup development and mortality.96 The same experiment stated that the no-observed-adverse-effect level of CA for pregnant female mice was 0.15 mg/kg/day.96 Therefore, high-dose CA should be cautioned in humans, especially pregnant women.

Several common limitations can be identified from the studies reviewed. Most studies did not adopt a positive control to compare against the anti-osteoclastogenesis or anti-osteoporosis effect of CA. Therefore, the therapeutic effects of CA and currently available anti-resorptive therapy cannot be compared. Although osteoblastogenesis and bone formation are also important in bone remodelling, evidence of CA on these processes is limited in the literature. The actions of CA in humans cannot be confirmed due to the lack of human clinical trials. These aspects can be improved in future studies.

The current review also has several limitations. We only considered articles indexed by PubMed, Scopus, Cochrane Library and Web of Science; therefore, non-indexed articles could be overlooked. We only selected articles studying CA or its derivatives as a single compound to understand its mechanism of action properly without other interference, but not a mixture of compounds or natural products rich in CA. CA are present in foods, and interaction with other compounds in the food matrix might alter its absorption, bioavailability and action on the target tissue. Moreover, the heterogeneous findings of CA in bone loss reduction upon oral administration further emphasise these possibilities.

The current preclinical evidence agrees that CA and its derivatives exert promising skeletal protective effects by inhibiting osteoclastogenesis and bone resorption, but literature on bone formation is limited. Notwithstanding that, the skeletal effects of CA and its derivatives in models of normal bone health should be investigated because the limited studies available show undesirable effects. Human clinical trials to validate the skeletal effects of CA are lacking. Therefore, a well-planned clinical trial should be conducted to confirm the potential of CA as an antiresorptive agent. This information is critical for CA and its derivatives to be incorporated as part of the strategies to prevent bone loss.

The researchers are funded by Universiti Kebangsaan Malaysia through Research University Grant (GUP-2020-021). S.O.E. and K.L.P. are post-doctoral researchers funded by Universiti Kebangsaan Malaysia through FPR-1 and RGA-1 grants.

The authors report no conflicts of interest in this work.

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Click to view a previous story about Carly's battle.

October 30th brought a second challenge to Vinton-Shellsburg Kindergarten teacher, Carly Meyer. After battling her first round of leukemia, she suffered another relapse with a second diagnosis of leukemia.

"I thought I was done with these updates... but should have known 2020 wasnt done messing stuff up yet!" Carly shared. "For those of you who don't know, I was diagnosed with Acute Myeloid Leukemia in August 2019 and completed chemo treatments in December 2019, but unfortunately my lab results on October 30, showed some "blasts", which are the cancerous cells in my blood." She explained back in November that her lab results also showed that my WBC's the infection fighting cells, were very low.

At the beginning of November, she had another bone marrow biopsy which Wes, her husband believes is her 6th. She was then admitted to the University of Iowa Hospital for a month long stay.

Carly finished up her 5 days of chemotherapy on November 11th with only a couple of side effects (fatigue and loss of appetite) which are a couple of the more common side effects with chemotherapy treatments. Unfortunately, she suffered from dehydration as well and this caused her to pass out a couple of times, and one of the falls caused her to hit her head. This of course triggered a trip for a CT Scan just to make sure she was alright, fortunately, she didn't have any side effects from the fall.

"It is fairly common for leukemia patients to spike fevers and to get random bugs because we are neutropenic and our body cant fight off simple things they normally would," Carly explained. She did come down with an infection during this time but it was able to be pinpointed and treated right away. On Thanksgiving, she was able to return home 10 days earlier from her hospital stay than had been anticipated,

Her journey continues to beat cancer with a trip back to the hospital at the end of December, to begin preparation for her bone marrow transplant. "My hero of a brother started getting shots December 30 to prep and will be donating his Stem Cells on Monday, January 4th." Carly explained how the process works. Her brother Kyle was hooked up to a machine she said it is similar to donating blood/plasma and that the procedure lasts for about 5 hours. Fortunately, her brother Kyle was a 100% perfect match to be her donor.

The stem cells were then put into her IV Powerline over about 30 minutes while they closely monitored Carly for any side effects. "Then its just a waiting game after that," she said.

After the transplant, Carly's immune system was down to zero. Unfortunately, it is common for SCT patients to spike fevers and even get an infection after transplant.

New Year, New Me has never rang more true than this year Carly said.

She is hoping to be home at the end of the week. She said that this last stay has been "extremely exhausting mentally and physically." Developing mucositis, extreme sores and pain in her mouth, it has made it very hard to eat or drink anything. Mucositis is very common after receiving the strong chemo that she received just before her bone marrow transplant. She is slowly recovering from this.

She said that she is excited to be coming home with her husband and fur-baby Maverick if all goes well, by the end of the week.

"I am so lucky to have an amazing support system (especially my husband) to get me through this tough time," she said.

Please keep the couple in your prayers as Carly continues to heal.

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BrainStorm Cell Therapeutics has announced that its NurOwn (MSC-NTF cell) derived exosomes provided significant improvement in lung function and histology in an acute respiratory distress syndrome (ARDS) mouse model, in a preclinical study.

Mesenchymal stem cell (MSC)-derived exosomes can penetrate deep into tissues and deliver immunomodulatory molecules effectively.

A type of respiratory failure, ARDS is linked to Covid-19 and is mediated by dysregulated cytokine production.

Intratracheal administration of NurOwn derived exosomes provided a statistically significant reduction in lung disease severity score, the study data showed.

Furthermore, improvements in lipopolysaccharide (LPS)-induced ARDS markers like lung function, fibrin presence, neutrophil accumulation, cytokine expression and oxygenation levels in the blood, were observed.

These improvements were significantly superior to those noticed following nave MSC-derived exosome administration.

BrainStorm Research and Development vice-president Dr Revital Aricha said: These exciting preclinical data suggest that NurOwn derived exosomes have the potential to treat Covid-19-induced ARDS or other severe respiratory complications and that they are more effective than exosomes isolated from nave MSCs at combatting the various symptoms of the syndrome.

This publication in a highly regarded journal provides important validation for the scientific advances and significance of BrainStorms preclinical research programs, including on our exosome-based technology platform.

The NurOwn technology platform (autologous MSC-NTF cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders.

GlobalData's TMT Themes 2021 Report tells you everything you need to know about disruptive tech themes and which companies are best placed to help you digitally transform your business.

MSC-NTF cells are made from autologous, bone marrow-derived MSCs expanded and separated ex vivo.

Brainstorm CEO Chaim Lebovits said: While our primary focus is on advancing NurOwn towards regulatory approval in ALS, we continue to evaluate the potential of our exosome-based platform to address unmet medical needs.

In December 2019, the company received a recommendation from the independent Data Safety Monitoring Board (DSMB) to continue the Phase II clinical trial of NurOwn in progressive multiple sclerosis patients.

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Large pharmaceutical companies have made gene therapy a priority with a series of acquisitions over the past several years, a stamp of validation for a field that's pushed through decades of ups and downs.

One of the latest buyers is German healthcare conglomerate Bayer, which in October inked a $2 billion deal for North Carolina gene therapy developer Asklepios Biopharmaceuticals, also known as AskBio.

For Bayer, the acquisition is part of a broader effort to build a gene and cell therapy division. But the deal is just as noteworthy for AskBio, an unusually large, privately held biotech based on the work of one of gene therapy's pioneers, Jude Samulski.

AskBio chose the security of a wealthy backer over independence and the chance to go public like several of its peers. And the deal helped the biotech quickly hire Katherine High, one of the few executives with experience shepherding a gene therapy through to regulatory approval. All of which makes the efforts of AskBio, now operating as an independent arm of Bayer, worth watching.

"I think we have the right people, the right chemistry, and the right amount of experience to make a difference here," Samulski said in an interview.

As 2019 drew to a close, so did a chapter in High's career. A hematologist by training, High, 69, has spent three decades working in gene therapy, a large portion of which was as a founder, president and chief scientific officer of Philadelphia biotech Spark Therapeutics.

At Spark, High had helped make history by steering the development of Luxturna, a treatment for a genetic form of blindness. When cleared by the Food and Drug Administration in late 2017, Luxturna became the first gene therapy for an inherited disease approved in the U.S. Roche swooped in soon after to acquire Spark, and closed the deal in December 2019.

Katherine High, president of therapeutics at AskBio

Permission granted by AskBio

High decided to take a year off from biopharma. But the coronavirus pandemic dashed her plans to conduct research at Rockefeller University. The institution reduced its staff to essential personnel, and the Harvard Club of New York City, where High, a Philadelphia resident, planned to stay during the week, closed its doors.

"My sabbatical turned into a virtual event, which was good; I got a lot of things done review articles written, book chapters written, things like that," High said in an interview. "I really needed a break."

She spent time with her first grandchild, swam, and, fulfilling a longtime desire, remotely studied German at Middlebury College's storied language program.

But High couldn't keep away from drug research. During periodic visits to North Carolina, where she has family, High dropped in on Samulski and fellow AskBio co-founder Sheila Mikhail.

High has over the years both collaborated and competed with Samulski, a University of North Carolina researcher and expert in gene therapy delivery tools known as adeno-associated viruses, or AAVs. He formed AskBio in 2001 with another gene therapy researcher, Xiao Xiao, and CEO Sheila Mikhail, a life sciences attorney.

"Our paths have crossed, our students have crossed, our sciences [have] definitely cross-pollinated," Samulski said, describing High's academic work at University of Pennsylvania and his at UNC.

By the time of their meeting, AskBio had grown to become one of the gene therapy field's most unique. Originally bootstrapped with angel investing and backing from the Muscular Dystrophy Association, AskBio had spun multiple gene therapy programs into companies that were later acquired. The returns from those buyouts were then used by AskBio to build its own manufacturing capabilities, a crucial step for gene therapy products.

During High's visits, Samulski and Mikail shared some of the progress the company had made advancing its technology. Among them: the acquisition of a Scottish biotech whose technology may allow the company to more tightly control how much protein a gene therapy can produce. Doing so could help overcome a critical limitations of gene therapy, which can have widely varying effects from patient to patient.

"We have a roadmap, how to get from A to B," Samulski told High. "If you want to come in and champion that, we would love to have you."

As AskBio was courting High, Bayer was eyeing AskBio, which had put in motion plans for an initial public offering a typical step for a biotech of its size.

Bayer had already announced plans to develop a cell and gene therapy division, acquiring Bluerock Therapeutics, a maker of "off-the-shelf" cell-based treatments, in 2019.

But the large pharma didn't have an anchor for its gene therapy ambitions. Marianne De Backer, Bayer's head of business strategy and development, had assembled a list of developers to pursue. AskBio was at the top.

"If you look at the [gene therapy] assets that are on the market today, like Zolgensma from Novartis, part of the technology is based on technology from AskBio," she said in an interview, referring to the Swiss company's spinal muscular atrophy treatment. A Duchenne muscular dystrophy treatment in late-stage testing at Pfizer also originated within AskBio, as did a Takeda program being studied in hemophilia.

De Backer faced two obstacles, though. Bayer, for one, didn't know the AskBio team, and couldn't meet them in person because of the travel restrictions that began during the pandemic.

"It was really almost a cold call," she said.

Bayer was also competing against the draw of a deep market for public stock offerings, which helped a record number of biotechs to IPO in 2020. De Backer said she needed to show AskBio that she could get the deal done quickly. So she and Mikhail spent six weeks hammering out terms, including an agreement the company could continue to operate independently an "arm's length" arrangement like one Bayer made with BlueRock.

Such promises are often made, and eventually broken, when a larger company acquires a smaller one. But Samulski's concerns that AskBio's work might be stifled within such a massive company were eased after speaking with BlueRock CEO Emile Nuwaysir.

Jude Samulski, co-founder and chief scientific officer at AskBio

Permission granted by AskBio

"[Nuwaysir] said, they have left me alone, they've encouraged me to do what I'm doing,' and I said, OK, that's what I needed to hear,'" Samulski said.

The acquisition allows the company to spend more time on science and less on raising money, he added.

"If I go back and write a grant today, it'll be three years before we can start the project," Samulski said. "In this setting, when we have our meeting ... the decision-makers are at the table and the science starts that afternoon."

For High, AskBio represents a return to a similar role as the one she had left: helping run an advanced gene therapy business newly acquired by big pharma. At AskBio, she's been named president of therapeutics.

The role, however, lines up with High's current career ambitions. AskBio has the manufacturing capabilities, breadth of clinical-stage programs and financial backing to take on diseases like Parkinson's and congestive heart failure the types of complex, common conditions gene therapy hasn't yet been proven in.

"There are great strengths in pharma, and there are great strengths in biotech, and the ideal situation is one that will let you employ the strengths of both types of organizations," she said.

High considered other options, such as working with a different and unproven drugmaking technology. But as someone who's spent much of her life living the story of gene therapy, she knows more than most the challenges of pioneering a new technology and convincing regulators of its worth.

Sometimes people "may underestimate the amount of time it takes to build all the tools that you need to enable regulators to say 'yes, this is safe,'" she said.

By sticking with gene therapy, much of the groundwork has been laid. She's just looking to take it a step further.

"I'm probably not going to work for another three decades," High said, with a laugh.

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How 2 scientific pioneers teamed up to run AskBio, Bayer's new gene therapy division - BioPharma Dive

However, the partners were not willing to disclose, as of today, which diseases exactly are being targeted under this alliance.

The collaborative project combines Neurogenes manufacturing and drug development capabilities with the University of Edinburghs novel platform and neurodevelopmental disease expertise.

Under the terms of the collaboration, the US company will provide financial support for Dr Stuart Cobbs laboratory at the University of Edinburgh, in exchange for the right to license any applicable intellectual property at agreed-upon economic terms.Neurogene will be responsible for late stage preclinical and all clinical development of any products generated under the collaboration.

Dr Cobbs lab uses a broad range of technologies to develop novel treatments for neurodevelopmental disorders based on a deep understanding of the molecular pathology.

In addition to Dr Cobbs position at the university, where he is a Simons fellow and reader in neuroscience, he is also Neurogenes chief scientific officer (CSO).

Neurogenes lead programs use adeno-associated virus (AAV) vector-based gene therapy technology to deliver a normal gene to patients with a dysfunctional gene. Its product pipeline of gene therapy candidates addresses distinct monogenic neurological diseases.

Neurogene is trying to find treatments for, among others, Batten disease - a group of rare, inherited diseases of the nervous system also called neuronal ceroid lipofuscinoses (NCLs).The company is focusing on CLN5 and CLN7, two rare, late infantile and rapidly progressive subtypes of Batten disease.Children with CLN5 or CLN7 typically develop signs and symptoms of the diseases at a young age, including seizures, progressive deterioration in intellectual and motor capabilities, and loss of vision.CLN5 is caused by a variant in the CLN5 gene, which leads to disruption of normal CLN5 protein function. The CLN7 subtype of Batten disease is caused by a variant in the CLN7 gene, also called the MFSD8 gene, which leads to disruption of normal CLN7 protein function.

Another disorder Neurogene is targeting is Charcot-Marie-Tooth disease (CMT) a group of inherited diseases that affect the peripheral nervous system (PNS). CMTs are the most common inherited motor and sensory nerve disorders - neuropathies.

It is also working to determine and address the root cause of diseases such as aspartylglucosaminuria (AGU) a rare, neurodegenerative lysosomal storage disorder (LSD).

In December 2020, Neurogene announced the completion of a US$115m Series B financing, which was led by EcoR1 Capital, with participation from existing investors Redmile Group, Samsara BioCapital, Cormorant Asset Management and an undisclosed leading healthcare investment fund.

New investors included funds and accounts managed by BlackRock, funds managed by Janus Henderson Investors, Casdin Capital, Avidity Partners, Ascendant BioCapital, Arrowmark Partners, and Alexandria Venture Investments.

The company said proceeds from the financing would be used to advance Neurogenes portfolio of multiple gene therapy programs into the clinic, as well as accelerate investment in novel gene therapy product designs and Neurogenes technology platform addressing key limitations in conventional gene therapy, while building out its AAV vector GMP manufacturing capabilities.

Oleg Nodelman, portfolio manager, EcoR1 Capital, said then: Neurogene is establishing itself as a leader in the gene therapy arena for neurological diseases. We are impressed by the companys innovation and accomplishments to date and are pleased to provide our support to Neurogene to advance medical research in this rapidly evolving area.

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Neurogene in tie up with university to advance gene therapy technologies - BioPharma-Reporter.com

Jan. 22, 2021, FNF Research (fnfresearch.com) published the latest study on [2020-2026] Cell and Gene Therapy Consumables Market Report by Quantitative Research Incorporating Impact Of Economic And Non-economic Aspects was recently released. It uses exploratory techniques like qualitative and quantitative analysis to uncover and present data on the target market. Efficient sales strategies have been mentioned that would business and multiply customers in record time.

This report is presented in a clear and concise way to help you better understand market structure and dynamics. Recent trends and developments in the Cell and Gene Therapy Consumables Market have been analyzed. Opportunities leading to market growth have been analyzed and stated. The report focuses on the global market and provides answers to the most important questions that stakeholders are facing today in the world. Information on the size of the market raises the issue of expanding competitiveness and hindering market-leading sectors and market growth.

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Key Questions Answered in this Report

The report also features information about significant market players across global regions that are North America, Europe, Latin America, Asia Pacific, and India. This further helps to enlighten the strong and effective business outlook of the industrial global expanse. Apart from paying attention to the present competitive current market scenario, the report also shares knowledge on the growth prospects of global Cell and Gene Therapy Consumables market during the forecast period of 2020-2026. The report also contains a circumstantiated description of various key vendors that are operating in the global regions. Showcasing a cosmopolitan landscape of Cell and Gene Therapy Consumables sector, the report marks the prevalent industry competition that is visible on both domestic as well as the global level.

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Competition Analysis

The global Cell and Gene Therapy Consumables market is divided on the basis of domains along with its competitors. Drivers and opportunities are elaborated along with their scope that helps to boosts the performance of the industries. It throws light on different leading key players to recognize the existing outline of Cell and Gene Therapy Consumables market. This report examines the ups and downs of the leading key players, which helps to maintain proper balance in the framework. Different global regions, such as Germany, South Africa, Asia Pacific, Japan, and China are analyzed for the study of productivity along with its scope. Moreover, this report marks the factors, which are responsible to increase the number of patrons at domestic as well as global level.

The Cell and Gene Therapy Consumables market is expected to grow in the upcoming 2020 to 2027 year. Different risks are considered, which helps to evaluate the complexity in the framework. The progress rate of global industries is mentioned to give a clear picture of business approaches. Various factors, which are responsible for the growth of the market are mentioned accurately. It gives a detailed description of drivers and opportunities in Cell and Gene Therapy Consumables market that helps the consumers and potential customers to get a clear vision and take effective decisions. Different analysis models, such as Cell and Gene Therapy Consumables are used to discover the desired data of the target market. In addition to this, it comprises various strategic planning techniques, which promote the way to define and develop the framework of the industries.

Regional outlook:

As per the research study by FNF Market Research, the global Cell and Gene Therapy Consumables market has fragmented across several regions such as North America, Latin America, Asia-Pacific, Africa, and Europe on the basis of key players. It covers the broad analysis of regional business overview including the financial overview.

Major industry key players have been documented to study successful strategies employed by leading industries.

Amgen Inc.

ATLANTA BIOLOGICALS

bluebird bio Inc.

Cook

Dendreon Pharmaceuticals LLC

Fibrocell Science Inc.

General Electric

Kolon TissueGene Inc.

Orchard Therapeutics plc.

Pfizer Inc.

PromoCell GmbH

RENOVA THERAPEUTICS

Sibiono GeneTech Co. Ltd.

Spark Therapeutics Inc.

Vericel

Helixmith Co. Ltd.

Vitrolife

Different market factors such as type, size, applications, and end-users have been included to study businesses thoroughly. Major pillars of the businesses that affect the ups and downs of Cell and Gene Therapy Consumables companies are also included in this report. The study has been aggregated on the basis of recent scope, challenges faced by businesses, and global opportunities to enlarge the Cell and Gene Therapy Consumables sector in upcoming years.

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To offer a holistic snapshot of global competition, different leading industry key players have been profiled to get better insights about the strategies adopted by them. The notable feature of this research report is, it gives more focus on strategies to discover the potential customers and to identify the global customers to enlarge the businesses.

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Cell and Gene Therapy Consumables Market 2020 Key Manufacturers, Development Trends and Competitive Analysis 2026 KSU | The Sentinel Newspaper - KSU...

Researchers have implicated the pro-inflammatory cytokine interleukin-1 (IL-1) in a wide variety of diseases such as osteoarthritis, rheumatoid arthritis (RA), diabetes, and obesity. Steven Abramson, MD, the Frederick H. King Professor of Internal Medicine, professor of pathology, and chair of the Department of Medicine at NYU Langone Health, has long studied how IL-1 can propagate and exacerbate the disease process. That research effort has more recently expanded to include investigations into how the anti-inflammatory IL-1 receptor antagonist, IL-1Ra, can counter IL-1 and modulate the inflammatory response. Based on intriguing findings about how certain gene variants may influence osteoarthritis risk and severity, a new National Institutes of Health (NIH) research grant will help Dr. Abramson and collaborators seek out IL-1related targets for inflammatory disease prevention and treatment.

To help clarify the inflammatory process, Dr. Abramson and collaborators including Mukundan G. Attur, PhD, associate professor of medicine, and Jonathan Samuels, MD, associate professor of medicine, examined several variants of the IL-1Raencoding IL1RN gene in the knee joints and cells of osteoarthritis and rheumatoid arthritis patients. In particular, a haplotype designated TTG predicted which at-risk patients would go on to develop knee osteoarthritis and was associated with more severe radiographic osteoarthritis as well as new onset RA. Its a marker of both severity and increased risk for incident osteoarthritis, Dr. Abramson says.

Their 2019 study in osteoarthritis patients, published in Annals of the Rheumatic Diseases, suggested that the IL1RN TTG haplotype produced less IL-1Ra protein. So one explanation for the finding is that these people with the gene are deficient in the endogenous inhibitor of IL-1, which is driving the disease, Dr. Abramson says. Conversely, a separate haplotype called CTA yields more IL-1Ra protein production and may be protective.

In collaboration with Jef D. Boeke, PhD, professor of biochemistry and molecular pharmacology and director of the Institute for Systems Genetics, a new NIH grant may help clarify how each gene haplotype modulates inflammation, influences the associated gene regulatory networks, and contributes to the mechanics of disease pathogenesis. In particular, the research will focus on a haplotype block, or a section of DNA including multiple genes adjacent to the IL1RN gene. The researchers hope to learn whether any of the neighboring genes have inflammatory properties of their own, a synergistic effect on IL1RN, or even a more dominant effect on the underlying inflammatory pathway. One reason to do that is if youre developing a drug, you might find that one of these other genes is a better target than IL1RN, Dr. Abramson says.

One key to the unique research effort is Dr. Boekes expertise in using CRISPR-Cas9 gene editing technology to construct a series of what his lab calls assemblons, or precisely altered haplotype blocks. Led by Dr. Attur, the collaborators will then transfect embryonic stem cells with the manipulated DNA and use in vitro assays to gauge the effects of the putative risk and protective IL1RN haplotypes. The genetic manipulation is very technical. But if we can succeed, it allows us to really define the role of these haplotypes, not just in osteoarthritis but in other IL-1driven diseases, Dr. Abramson says.

After differentiating the engineered embryonic stem cells into macrophage cells, the researchers will measure production of the IL-1Ra protein. Well also be stimulating the macrophages in an inflammatory way and looking at the profile of inflammatory mediators that they produce, Dr. Abramson says. Experiments may reveal whether stimulated macrophages that carry the protective IL1RN CTA haplotype, for example, produce more IL1-Ra protein and fewer pro-inflammatory mediators such as IL-1, cyclooxygenase-2 (COX-2), and tumor necrosis factor (TNF). In the same way, sequential knockouts of other genes in the assemblon may clarify their own contributions to each haplotypes effects.

If the researchers can zero in on the principal drivers of disease through their in vitro experiments, they plan to inject the engineered embryonic stem cells into mice models of osteoarthritis and RA. The in vivo studies of the gene regulatory network may help determine how specific gene variants influence disease outcomes.

The research could have broad implications for understanding IL-1associated inflammatory diseases and for personalizing antiIL-1 therapies. It might be that in personalized medicine, antiIL-1 treatments will be more effective in patients who have a deficiency of IL-1 receptor antagonist, Dr. Abramson says. A patient who produces abundant IL-1Ra, on the other hand, may not benefit from receiving more of it as a therapy. Alternatively, the research may suggest that the IL1RN haplotypes are exerting their influence mainly by modulating other genes with key roles in the disease pathogenesis. It may be that they will emerge as targets that people hadnt even thought about in those diseases, he says.

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New Research Grant Seeks to Clarify the Role Genes Play in Modulating Inflammation - NYU Langone Health

INDIANAPOLIS, Jan. 22, 2021 /PRNewswire/ --Eli Lilly and Company (NYSE:LLY) today announced the successful completion of its acquisition of Prevail Therapeutics Inc. (NASDAQ: PRVL). The acquisition establishes a new modality for drug discovery and development at Lilly, extending Lilly's research efforts through the creation of a gene therapy program that will be anchored by Prevail's portfolio of clinical-stage and preclinical neuroscience assets.

"We are pleased to complete the acquisition of Prevail and establish a gene therapy program at Lilly that has the potential to deliver transformative treatments for patients with neurodegenerative diseases such as Parkinson's, Gaucher and dementia," said Mark Mintun, M.D., vice president of pain and neurodegeneration research at Lilly.

The impact of this transaction will be reflected in Lilly's 2021 financial results according to Generally Accepted Accounting Principles (GAAP). There will be no change to Lilly's 2021 financial guidance for research and development expense or non-GAAP earnings per share as a result of this transaction.

The Offer and the MergerThe tender offer for all of the outstanding shares of common stock of Prevail at a price of (i) $22.50 per share, net to the seller in cash, without interest and less any applicable tax withholding, plus (ii) one non-tradable contingent value right (a "CVR"), which CVR represents the contractual right to receive a contingent payment of up to $4.00 per share, net to the seller in cash, without interest and less any applicable tax withholding, which amount (or such lesser amount, as further described below) will become payable, if at all, if a specified milestone is achieved prior to December 1, 2028 (the "Offer"), expired as scheduled at one minute past 11:59 p.m., Eastern time, on January 21, 2021. Computershare Trust Company, N.A., the depositary and paying agent for the Offer, has advised Lilly that27,374,689 shares of Prevail common stock were validly tendered and not properly withdrawn in the Offer, representing approximately79.8 percent of the shares of Prevail common stock outstanding. All of the conditions to the Offer have been satisfied, and on January 22, 2021, Lilly and its wholly-owned subsidiary, Tyto Acquisition Corporation, accepted for payment, and will promptly pay for, all shares validly tendered and not properly withdrawn in the Offer.

Following completion of the Offer, Lilly completed the acquisition of Prevail through the merger of Tyto Acquisition Corporation with and into Prevail, without a vote of Prevail's stockholders pursuant to Section 251(h) of the General Corporation Law of the State of Delaware, with Prevail surviving the merger as a wholly-owned subsidiary of Lilly. In connection with the merger, each share of common stock of Prevail not validly tendered in the Offer (other than (1) shares owned by Prevail (or held in Prevail's treasury) immediately prior to the effective time of the merger, (2) shares owned by Lilly, Tyto Acquisition Corporation or any other wholly owned subsidiary of Lilly immediately prior to the effective time of the merger or (3) shares held by any stockholder that was entitled to and has properly demanded statutory appraisal of such shares pursuant to, and who complied in all respects with, Section 262 of the Delaware General Corporation Law (the "DGCL") and who, as of the effective time of the merger, had neither effectively withdrawn nor lost its rights to such appraisal and payment under the DGCL with respect to such shares) has been cancelled and converted into the right to receive the same (i) $22.50 per share in cash, without interest and less applicable tax withholding, plus (ii) one CVR, as will be paid for all shares that were validly tendered and not properly withdrawn in the Offer. Prevail's common stock will be delisted from the NASDAQ Stock Market.

Under the terms of the agreement, Prevail stockholders were awarded one non-tradable CVR worth up to $4.00 per share in cash payable (subject to certain terms and conditions) upon the first regulatory approval for commercial sale of a Prevail product in one of the following countries: United States, Japan, United Kingdom, Germany, France, Italy or Spain. To achieve the full value of the CVR, such regulatory approval must occur by December 31, 2024. If such regulatory approval occurs after December 31, 2024, the value of the CVR will be reduced by approximately 8.3 cents per month until December 1, 2028 (at which point the CVR will expire). There can be no assurance any payments will be made with respect to the CVR.

About Eli Lilly and CompanyLilly is a global healthcare leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at http://www.lilly.com. C-LLY

Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements about Lilly's acquisition of Prevail Therapeutics Inc. ("Prevail"), regarding contingent consideration amounts and terms, regarding Prevail's product candidates and ongoing preclinical development, regarding Lilly's development of a potential gene therapy program, and regarding Lilly's expected 2021 financial guidance and the impact of the acquisition on research and development expense and non-GAAP earnings per share. It reflects current beliefs and expectations; however, as with any such undertaking, there are substantial risks and uncertainties in integration of acquisitions, in drug research, development and commercialization, and in Lilly's evaluation of its estimated financial results for 2021 and the impact of the acquisition. Actual results could differ materially due to various factors, risks and uncertainties. Among other things, there can be no guarantee that Lilly will realize the expected benefits of the acquisition, that product candidates will be approved on anticipated timelines or at all, that Lilly will be successful in building a gene therapy program, that any products, if approved, will be commercially successful, that all or any of the contingent consideration will become payable on the terms described herein or at all, that Lilly's financial results will be consistent with its expected 2021 guidance or that Lilly can reliably predict the impact of the acquisition on its 2021 financial guidance and results. For further discussion of these and other risks and uncertainties, see Lilly's most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission (the "SEC"). Except as required by law, Lilly does not undertake any duty to update forward-looking statements to reflect events after the date of this press release.

Refer to:

Mark Taylor; mark.taylor@lilly.com; (317) 276-5795 (Media)

Kevin Hern; hern_kevin_r@lilly.com; (317) 277-1838 (Investors)

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Lilly Completes Acquisition of Prevail Therapeutics - BioSpace

Databridgemarketresearch.com Present Cancer Gene Therapy Market Industry Trends and Forecast to 2027 new report to its research database. This report is always helpful to business or organization in every subject of trade for taking better decisions, solving the toughest business questions and minimizing the risk of failure. The studies of this report carefully analyzes the market status, growth rate, future trends, market drivers, opportunities, challenges, risks, entry barriers, sales channels, and distributors. The most advanced tools and techniques have been used to structure this Cancer Gene Therapy Market report such as SWOT analysis and Porters Five Forces Analysis. Moreover, different segments of the market taken into consideration in this market research report give better market insights with which reach to the success gets extended.

Cancer gene therapy market is expected to gain market growth in the forecast period of 2020 to 2027. Data Bridge Market Research analyses the market to account to USD 6407.88 million by 2027 growing with the CAGR of 32.54% in the above-mentioned forecast period. The high success rate of cancer gene therapy along with clinical trial and preclinical trial is gaining popularity among the patient which is leading towards the market.

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The major players covered in the cancer gene therapy market report are Adaptimmune, GlaxoSmithKline plc, bluebird bio, Inc, Merck & Co., Inc., CELGENE CORPORATION, Anchiano Therapeutics, Achieve Life Sciences, Inc among other domestic and global players.

Competitive Landscape and Cancer Gene Therapy Market Share Analysis

Cancer gene therapy market competitive landscape provides details by competitor. Details included are company overview, company financials, revenue generated, market potential, investment in research and development, new market initiatives, global presence, production sites and facilities, production capacities, company strengths and weaknesses, product launch, product width and breadth, application dominance. The above data points provided are only related to the companies focus related to cancer gene therapy market.

Global Cancer Gene Therapy Market Scope and Market Size

Cancer gene therapy market is segmented on the basis of therapy and end user. The growth amongst these segments will help you analyse meagre growth segments in the industries, and provide the users with valuable market overview and market insights to help them in making strategic decisions for identification of core market applications.

Increase in funding of research and development in the activities of cancer gene therapy along with rise in prevalence of cancer is likely to accelerate the growth of the cancer gene therapy market in the forecast period of 2020-2027. On the other hand, the favourable government regulations for therapy is further going to boost various opportunities that will lead to the growth of the cancer gene therapy market in the above mentioned forecast period.

High cost involved in gene therapy along with unwanted immune responses wills likely to hamper the growth of the cancer gene therapy market in the above mentioned forecast period.

This cancer gene therapy market report provides details of new recent developments, trade regulations, import export analysis, production analysis, value chain optimization, market share, impact of domestic and localised market players, analyses opportunities in terms of emerging revenue pockets, changes in market regulations, strategic market growth analysis, market size, category market growths, application niches and dominance, product approvals, product launches, geographical expansions, technological innovations in the market. To gain more info on Cancer gene therapy market contactData Bridge Market Researchfor anAnalyst Brief, our team will help you take an informed market decision to achieve market growth.

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Cancer Gene Therapy Market Country Level Analysis

Cancer gene therapy market is analysed and market size insights and trends are provided by country, therapy and end user as referenced above.

The countries covered in the cancer gene therapy market report are U.S., Canada and Mexico in North America, Germany, France, U.K., Netherlands, Switzerland, Belgium, Russia, Italy, Spain, Turkey, Rest of Europe in Europe, China, Japan, India, South Korea, Singapore, Malaysia, Australia, Thailand, Indonesia, Philippines, Rest of Asia-Pacific (APAC) in the Asia-Pacific (APAC), Saudi Arabia, U.A.E, South Africa, Egypt, Israel, Rest of Middle East and Africa (MEA) as a part of Middle East and Africa (MEA), Brazil, Argentina and Rest of South America as part of South America.

North America dominates the cancer gene therapy market due to the advanced healthcare infrastructure along with rise in R & D expenditure, while Asia-Pacific is expected to grow with the highest growth rate in the forecast period of 2020 to 2027 due to the improving healthcare infrastructure and government initiatives.

The country section of the cancer gene therapy market report also provides individual market impacting factors and changes in regulation in the market domestically that impacts the current and future trends of the market. Data points such as consumption volumes, production sites and volumes, import export analysis, price trend analysis, cost of raw materials, down-stream and upstream value chain analysis are some of the major pointers used to forecast the market scenario for individual countries. Also, presence and availability of global brands and their challenges faced due to large or scarce competition from local and domestic brands, impact of domestic tariffs and trade routes are considered while providing forecast analysis of the country data.

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Healthcare Infrastructure Growth Installed Base and New Technology Penetration

Cancer gene therapy market also provides you with detailed market analysis for every country growth in healthcare expenditure for capital equipment, installed base of different kind of products for cancer gene therapy market, impact of technology using life line curves and changes in healthcare regulatory scenarios and their impact on the cancer gene therapy market. The data is available for historic period 2010 to 2018.

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Cancer Gene Therapy Market : Future Prospects With Covid-19 Impact Analysis 2027 | Top Players- Adaptimmune, GlaxoSmithKline plc, bluebird bio, Inc -...

GlobalGene TherapyMarket Research Report and Forecast 2020-2025is the latest report byFior Marketswhich is the fastest growing market research company. The report provides a comprehensive scope of the market which includes future supply and demand scenarios, changing market trends, high growth opportunities, and in-depth analysis of the future market prospects. The report features real-time developments in the globalGene Therapymarket encompasses a highly structured and comprehensive outlook of the market. It shows market types and applications that are categorized as ideal market segments. The report covers the competitive data analysis of the emerging and prominent players of the market. Along with this, it provides comprehensive data analysis on the risk factors, challenges, and possible new market avenues.

The report has viewed the current top players and the forthcoming contenders. Business procedures of the vital participants and the new entering market ventures are concentrated in detail in this report. The report also encompasses SWOT investigation, income offer, and contact data. The report throws light on specific drivers, restraints, opportunities, challenges, and other determinants that tremendously favor and oppose normal growth in the globalGene Therapymarket. It also covers the product pricing factors, growth, emerging and dominant trends, overall market dynamics, and market size. The report includes a wide spectrum of the market to provide insightful data for the forecast period 2020-2025.

NOTE:Our analysts monitoring the situation across the globe explains that the market will generate remunerative prospects for producers post the COVID-19 crisis. The report aims to provide an additional illustration of the latest scenario, economic slowdown, and COVID-19 impact on the overall industry.

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The report gives the market segments that have been fragmented into sub-segments. The study gives a transparent view of the global market and includes a thorough competitive scenario and portfolio of the key players functioning in it. The report offers fundamental opinions regarding the market landscape, emerging and high-growth sections of the globalGene Therapymarket, high-growth regions, and market drivers, restraints, and also market chances. It targets estimating the current market size and growth potential of the global market across sections such as also applications and representatives.

Competitive Analysis:

Te report accurately profiles key vendors and players functioning in the globalGene Therapymarket, in terms of their ranking and core competencies, together with determining the competitive landscape. It also studies competitive developments such as partnerships and collaborations, mergers, and acquisitions (M&A), research and development (R&D) activities, product developments, and expansions in the global market.

The top key players profiled in this report are:Spark Therapeutics LLC, Bluebird Bio, UniQure N.V., Juno Therapeutics, GlaxoSmithKline, Chiesi Farmaceutici S.p.A., Bristol Myers Squibb, Celgene Corporation, Human Stem Cell Institute, Voyager Therapeutics, Shire Plc, Sangamo Biosciences, Dimension Therapeutics

Other Segment Analysis:

Segment classification of the market structure has been encouraged by our research experts to allow readers to comprehend the versatility of the market in terms of product and service variation. The market has been examined with vital market-specific developments across segment categories. Market segments such as type and application are also determined by quantitative and qualitative review. Type market size bifurcated into its product typeGermline Gene Therapy and Somatic Gene Therapyin terms of Volume (K Units) and Value (USD Million). Market segment by application, split into:Cardio Vascular Diseases, Infectious Diseases, Genetic Disorders, Neuro Disorders, Cancer, Others

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The report presents an understanding of the regional, country, and even local developments. Overview of globalGene Therapy market dynamics such as industry outlook, value chain developments, SWOT and PESTEL assessment as well as Porters Five Point analysis. The report also encompasses crucial analytical reviews on key elements, trends, current, and future perspectives. By regional analysis, the report covers:North America, Europe, Asia Pacific, South America, and the Middle East and Africa.

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Global Gene Therapy Market Worth $38.41 Million by 2025- Exclusive Report by Fior Markets - PharmiWeb.com

LabCorps contract research organization business Covance has promoted Maryland Franklin, Ph.D., to vice president and head of its cell and gene therapy unit.

She moves up from being Covances site lead and executive director of scientific development at the Ann Arbor, Michigan, facility, which focuses on preclinical oncology.

Now, she steps up to run its cell and gene therapy business, a major element in any CRO's portfolio these days as more and more biopharmas look to tap the therapies for potentially curative treatments for a range of diseases.

It remains a tricky proposition to pull off, but cell and gene therapy are very much the current course for R&D across the life sciences as well as a major part of Covances business. Under her new role, Franklin will oversee these offerings.

These solutions aim to help sponsors reduce risk, transition programs within and between phases of development faster and create a more patient-centric experience, Covance said in a statement, as Franklin will also be tapped to further extend Covance by Labcorps industry leading position.

RELATED: Covance to 'transform' into a decentralized CRO

We are thrilled to welcome Dr. Franklin to Covance by Labcorp. Her experience and expertise will bring perspective and insight to cell and gene therapy at Covance, said Bill Hanlon, Ph.D., president of clinical, therapeutic and regulatory sciences for Covance.

Dr. Franklin joins us at a critical juncture in our ability to support sponsors needs throughout the drug development process. She will guide our highly experienced scientists across functional disciplines to seamlessly develop and commercialize a cell or gene therapy. With Dr. Franklins expertise, we hope to further grow and advance our cell and gene therapy programs.

Cell and gene therapy approaches continue to show great promise in treating a variety of diseases that range from extremely debilitating rare diseases to applications in oncology, added Franklin. With several approved advanced therapies to date and many, many more in development, Im excited to join Covance by Labcorp to and help sponsors in their mission to improve the lives of patients.

.

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Covance boosts Franklin to lead its cell and gene therapy unit - FierceBiotech

Cancer gene therapy is a technique used for the treatment of cancer where therapeutic DNA is being introduced into the gene of the patient with cancer. Due to the high success rate during the preclinical and clinical trial, cancer gene therapy is gaining popularity. There are many techniques used for cancer gene therapy, for example, a procedure where the mutated gene is being replaced with a healthy gene or inactivation of gene whose function is abnormal. Recently, a new technique has been developed, where new genes are introduced into the body to help fight against cancer cells.

The global Cancer Gene Therapy market is expected to expand at a CAGR of +32% over the forecast period 2019-2025.

The report, titled Global Cancer Gene Therapy market defines and briefs readers about its products, applications, and specifications. The research lists key companies operating in the global market and also highlights the key changing trends adopted by the companies to maintain their dominance. By using SWOT analysis and Porters five force analysis tools, the strengths, weaknesses, opportunities, and threats of key companies are all mentioned in the report. All leading players in this global market are profiled with details such as product types, business overview, sales, manufacturing base, competitors, applications, and specifications.

Top Key Vendors in Market:

Genelux Corporation, Cell Genesys, Advantagene, GenVec, BioCancell, Celgene, Epeius Biotechnologies, Introgen Therapeutics, Ziopharm Oncology, Shenzhen SiBiono GeneTech, and Altor Bioscience.

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Cancer Gene Therapy market has been studied in terms of all parameters such as applications, types, products and many other. Each and every data leading to growth or fall of the respective segments have been explained. Entire supply chain with respect to market is studied in depth and is conveyed in the most comprehensive way possible. The reasons there is going to be an increasing trend to this market are studied and are elaborated. Driving forces, restraints and opportunities are given to help give a better picture of this market investment for the forecast period.

Different global regions such as North America, Latin America, Asia-Pacific, Europe, and India have been analyzed on the basis of the manufacturing base, productivity, and profit margin. This Cancer Gene Therapy market research report has been scrutinized on the basis of different practical oriented case studies from various industry experts and policymakers. It uses numerous graphical presentation techniques such as tables, charts, graphs, pictures and flowchart for easy and better understanding to the readers.

The reports conclusion leads into the overall scope of the global market with respect to feasibility of investments in various segments of the market, along with a descriptive passage that outlines the feasibility of new projects that might succeed in the global Cancer Gene Therapy market in the near future.

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Key questions answered in the report include:

Table of Content:

Global Cancer Gene Therapy Market Research Report 2019-2025

Chapter 1: Industry Overview

Chapter 2: Cancer Gene Therapy Market International and China Market Analysis

Chapter 3: Analysis of Revenue by Classifications

Chapter 4: Analysis of Revenue by Regions and Applications

Chapter 5: Analysis of Cancer Gene Therapy Market Revenue Market Status.

Chapter 6: Sales Price and Gross Margin Analysis

Continue for TOC..

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Explore why Cancer Gene Therapy Market is thriving by 2025 with top key players like Genelux Corporation, Cell Genesys, Advantagene, GenVec,...

New York, Jan. 22, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Transient Protein Expression Market Forecast to 2027 - COVID-19 Impact and Global Analysis By Product Type ; Application ; End User, and Geography." - https://www.reportlinker.com/p06010110/?utm_source=GNW However, high cost of products are likely to pose a negative impact on the market growth.Transient protein expression procedure has been widely in use for animal and plant cells for the last three decades.However, in the recent years, significant evolution in proteomics has resulted in the development of recombinant proteins.

The effective results of transient protein expression in animals and plants have increased research and product development for human applications.Various companies, including biopharmaceuticals and contract research and development organizations have channelized their efforts toward the development of products based on transient protein expression.The adoption of transient protein expression allow companies to get various genes to develop recombinant proteins without delaying cell line generation.

Thus, the quick process of cell line development with required gene expression, companies are widely attracted towards uniform proteins that have drug-like properties, which allows production of vaccines and viral vectors. In addition, the transient protein expression process is widely being used in the production of monoclonal antibodies, modified human proteins, growth factors and cytokines, hormones, and blood products.The COVID19 pandemic has resulted in rise in the use of transient protein expression in vaccine development.Various researchers have started studying the novel coronavirus extensively, with the use of transient protein expression.

For instance, in MarchApril 2020, Absolute Antibody (UK) increased the production of multigram quantities of multiple anti-SARS-CoV-2 spike proteins to develop neutralizing antibodies. Similarly, the transient protein expression was widely used to produce a positive control protein in the development of in-vitro diagnostics kits.Product Type InsightsThe transient protein expression market by product type is segmented into instruments, reagents, vectors, and competent cells.In 2019, instruments segment held a largest market share in the transient protein expression market, by product type.

This segment is also expected to dominate the market in 2027 as they are the reducing human input is that it enables continuous cell maintenance and protein production. Moreover, the similar segment is anticipated to also witness the fastest growth rate during the forecast period.

Application InsightsBased on application, the global transient protein expression market is segmented into genomic research, gene therapy, bio production, cancer research, and drug development.In 2019, the genomic research segment held the largest market share in the transient protein expression market.

This segment is also expected to dominate the market by 2027 as it increases DNA sequencing performance. Moreover, transient protein expression has helped in the study of all the genes of a person (the genome), including their interactions with each other as well as the environment.

End User InsightsIn terms of end user, the global transient protein expression market is segmented into pharmaceutical and biotechnology companies, academic and research institutes, and clinical research organizations.In 2019, the pharmaceutical and biotechnology companies segment held the largest market share.

This segment is also expected to dominate the market during the forecast period as pharmaceutical and biotechnology firms are increasing their spending on research and R&D activities. Moreover, transient protein expression has helped the recent improvements in existing technologies and it is moving toward industrial production of plant-based vaccines, antibodies, and biopharmaceuticals.Major primary and secondary sources for transient protein expression included in the report are National Research Council Canada, UK BioIndustry Association, Australian Cluster Observatory and McKell Institute, UAE Federal Customs Authority, and Alpen Capitals report, among others.Read the full report: https://www.reportlinker.com/p06010110/?utm_source=GNW

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The global transient protein expression market is expected to reach US$ 983.10 million by 2027 from US$ 660.00 million in 2019 - GlobeNewswire

New York, Jan. 18, 2021 (GLOBE NEWSWIRE) -- Increased investment in advanced technologies for treatment of genetic and chronic diseases is driving growth of the regenerative medicine market.Market Size USD 7.34 Billion in 2019, Market Growth - CAGR of 15.6%, Market TrendsApplications in COVID-19 vaccine.

The global regenerative medicine market is forecast to reach a market size of USD 23.57 Billion by 2027, and register a robustly incline revenue growth, according to a new report by Reports and Data. Primary factors driving demand for regenerative medicines are advancements in surgical technology and monitoring devices, and major increase in prevalence of complex and degenerative diseases. Upsurge in incidence of cancers has been resulting in increasing research into stem cell therapy. Growth in research and development activities in emerging countries and rising focus on stem cell research is resulting in significant growth in the global revenue of regenerative medicine market.

Stem cell technology is growing rapidly and continues to play a crucial role in regenerative medicine and the related field. This technology opens up the possibility of treating Parkinsons Disease, arthritis, and spinal cord injury. Increase in demand for stem cell technology is a major factor driving growth of the regenerative medicine market.

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Recent developments in regenerative medicine for 3D bioprinting, stem cell treatment for heart repair, and vision loss has created demand for additional investments in the R&D of the technology to help with other diseases.

The COVID-19 impact:

Demand for regenerative medicine has witnessed increased demand during the COVID-19 pandemic. Regenerative medicine helps in understanding a mechanism of infection and to develop ways to prevent the spread of the virus. It is also being used to create advanced treatments to treat persons infected by the COVID-19 virus. Private companies are also using it to develop an effective vaccine for COVID-19.

Regenerative Medicine Market Size, Share & Industry Demand By Product (Tissue-Engineered Products, Cell Therapies, Gene Therapies, Progenitor & Stem Cell Therapies), By Application (Musculoskeletal Disorders, Oncology, Wound Care, By Material), and Region, Segment Forecast to 2027, To identify the key trends in the industry, click on the link below: https://www.reportsanddata.com/report-detail/regenerative-medicine-market

Further key findings from the report suggest

List of Key Companies Identified in the Regenerative Medicine Market Report:

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For the purpose of this report, Reports and Data has segmented into the global regenerative medicine market on the basis of product, application, material, and region:

Browse similar research reports:Cell Therapy Market By Therapy Type (Allogeneic Stem Cell Therapy, Autologous Stem Cell Therapy), By Therapeutic Area (Malignancies, Autoimmune Disorders, Musculoskeletal Disorders), By Cell Type, And By End User, Forecasts To 2027

Tissue Engineering Market Size, Growth & Analysis, By Material, By Application (Cancer, Urology, Neurology, Dental, Cell Banking & Cord Blood, Gynecology, Integumentary/Skin, Spine, Musculoskeletal, & Orthopedics, Vascular & Cardiology), And Region, Segment Forecasts To 2027

Gene Expression Market By Product And Services (Equipment, Consumables, And Services), By Capacity (Low- To Mid- Plex Gene Expression Analysis And High-Plex Gene Expression Analysis), By Application (Diagnostic, Drug Discovery, Research), And Segment Forecasts To 2027

About Reports and Data

Reports and Data is a market research and consulting company that provides syndicated research reports, customized research reports, and consulting services. Our solutions purely focus on your purpose to locate, target and analyze consumer behavior shifts across demographics, across industries and help clients make a smarter business decision. We offer market intelligence studies ensuring relevant and fact-based research across a multiple industries including Healthcare, Technology, Chemicals, Power, and Energy. We consistently update our research offerings to ensure our clients are aware about the latest trends existent in the market. Reports and Data has a strong base of experienced analysts from varied areas of expertise.

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Regenerative Medicine Market Size Worth $23.57 Bn By 2027; High demand for 3D bioprinting of tissues and organs to better understand their mechanism...

Databridgemarketresearch.com Present Cancer Gene Therapy Market Industry Trends and Forecast to 2027 new report to its research database. This analysis offers an examination of a range of segments that are relied upon to witness the quickest development amid the estimate forecast frame. The company profiles of all the key players and brands that are dominating the Cancer Gene Therapy Market with moves like product launches, joint ventures, mergers and acquisitions which in turn is affecting the sales, import, export, revenue and CAGR values are mentioned in the report. A complete discussion about numerous market related topics in this research report is sure to aid the client in studying the market on competitive landscape. This report also gives you an idea about consumers demands, preferences, and their altering likings about particular product.

Cancer gene therapy market is expected to gain market growth in the forecast period of 2020 to 2027. Data Bridge Market Research analyses the market to account to USD 6407.88 million by 2027 growing with the CAGR of 32.54% in the above-mentioned forecast period. The high success rate of cancer gene therapy along with clinical trial and preclinical trial is gaining popularity among the patient which is leading towards the market.

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The major players covered in the cancer gene therapy market report are Adaptimmune, GlaxoSmithKline plc, bluebird bio, Inc, Merck & Co., Inc., CELGENE CORPORATION, Anchiano Therapeutics, Achieve Life Sciences, Inc among other domestic and global players.

Competitive Landscape and Cancer Gene Therapy Market Share Analysis

Cancer gene therapy market competitive landscape provides details by competitor. Details included are company overview, company financials, revenue generated, market potential, investment in research and development, new market initiatives, global presence, production sites and facilities, production capacities, company strengths and weaknesses, product launch, product width and breadth, application dominance. The above data points provided are only related to the companies focus related to cancer gene therapy market.

Global Cancer Gene Therapy Market Scope and Market Size

Cancer gene therapy market is segmented on the basis of therapy and end user. The growth amongst these segments will help you analyse meagre growth segments in the industries, and provide the users with valuable market overview and market insights to help them in making strategic decisions for identification of core market applications.

Increase in funding of research and development in the activities of cancer gene therapy along with rise in prevalence of cancer is likely to accelerate the growth of the cancer gene therapy market in the forecast period of 2020-2027. On the other hand, the favourable government regulations for therapy is further going to boost various opportunities that will lead to the growth of the cancer gene therapy market in the above mentioned forecast period.

High cost involved in gene therapy along with unwanted immune responses wills likely to hamper the growth of the cancer gene therapy market in the above mentioned forecast period.

This cancer gene therapy market report provides details of new recent developments, trade regulations, import export analysis, production analysis, value chain optimization, market share, impact of domestic and localised market players, analyses opportunities in terms of emerging revenue pockets, changes in market regulations, strategic market growth analysis, market size, category market growths, application niches and dominance, product approvals, product launches, geographical expansions, technological innovations in the market. To gain more info on Cancer gene therapy market contactData Bridge Market Researchfor anAnalyst Brief, our team will help you take an informed market decision to achieve market growth.

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Cancer Gene Therapy Market Country Level Analysis

Cancer gene therapy market is analysed and market size insights and trends are provided by country, therapy and end user as referenced above.

The countries covered in the cancer gene therapy market report are U.S., Canada and Mexico in North America, Germany, France, U.K., Netherlands, Switzerland, Belgium, Russia, Italy, Spain, Turkey, Rest of Europe in Europe, China, Japan, India, South Korea, Singapore, Malaysia, Australia, Thailand, Indonesia, Philippines, Rest of Asia-Pacific (APAC) in the Asia-Pacific (APAC), Saudi Arabia, U.A.E, South Africa, Egypt, Israel, Rest of Middle East and Africa (MEA) as a part of Middle East and Africa (MEA), Brazil, Argentina and Rest of South America as part of South America.

North America dominates the cancer gene therapy market due to the advanced healthcare infrastructure along with rise in R & D expenditure, while Asia-Pacific is expected to grow with the highest growth rate in the forecast period of 2020 to 2027 due to the improving healthcare infrastructure and government initiatives.

The country section of the cancer gene therapy market report also provides individual market impacting factors and changes in regulation in the market domestically that impacts the current and future trends of the market. Data points such as consumption volumes, production sites and volumes, import export analysis, price trend analysis, cost of raw materials, down-stream and upstream value chain analysis are some of the major pointers used to forecast the market scenario for individual countries. Also, presence and availability of global brands and their challenges faced due to large or scarce competition from local and domestic brands, impact of domestic tariffs and trade routes are considered while providing forecast analysis of the country data.

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Healthcare Infrastructure Growth Installed Base and New Technology Penetration

Cancer gene therapy market also provides you with detailed market analysis for every country growth in healthcare expenditure for capital equipment, installed base of different kind of products for cancer gene therapy market, impact of technology using life line curves and changes in healthcare regulatory scenarios and their impact on the cancer gene therapy market. The data is available for historic period 2010 to 2018.

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Cancer Gene Therapy Market Segmentation, Parameters, Prospects 2021 And Forecast Research Report To 2027 - The Courier

DALLAS--(BUSINESS WIRE)--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, today announced that it has received both rare pediatric disease and orphan drug designations from the U.S. Food and Drug Administration (FDA) for TSHA-105, an AAV9-based gene therapy in development for SLC13A5-related epilepsy.

There are no approved therapies for epilepsy caused by SLC13A5 that address the underlying cause of this disease, said RA Session II, President, Founder and CEO of Taysha. We are encouraged by the early evidence of TSHA-105s disease-modifying approach and believe these designations will help us potentially accelerate the development of this exciting program. We look forward to working with the FDA to make TSHA-105 available to patients as expeditiously as possible.

SLC13A5 is a form of infantile epilepsy caused by mutations in the SLC13A5 gene. The disorder is an autosomal recessive disorder, so two copies of the mutated gene must be inherited to affect an infant. This rare form of epilepsy manifests as developmental delay, and seizures beginning within the first few days of life.

We are pleased that the FDA recognizes TSHA-105s potential as an innovative therapeutic option for SLC13A5 deficiency, said Rachel Bailey, Ph.D., Assistant Professor in Pediatric Neurology at UT Southwestern. This disease is a debilitating form of genetic epilepsy in children that significantly impacts movement, motor control, cognition and quality of life, and there remains a need to alter the course of this disease early in life.

As a mother of two children with SLC13A5 deficiency, I have witnessed firsthand the devastating impact that numerous seizures and comorbidities accompanying the disease has on those affected by this disease, said Kim Nye, Founder of TESS Research Foundation. Tayshas commitment to developing a potentially life-changing gene therapy for SLC13A5 deficiency is greatly welcomed by our patient community.

The FDA grants rare pediatric disease designation for serious and life-threatening diseases that primarily affect children ages 18 years or younger and fewer than 200,000 people in the United States. The Rare Pediatric Disease Priority Review Voucher Program is intended to address the challenges that drug companies face when developing treatments for these unique patient populations. Under this program, companies are eligible to receive a priority review voucher following approval of a product with rare pediatric disease designation if the marketing application submitted for the product satisfies certain conditions, including approval prior to September 30, 2026 unless changed by legislation. If issued, a sponsor may redeem a priority review voucher for priority review of a subsequent marketing application for a different product candidate, or the priority review voucher could be sold or transferred to another sponsor.

Orphan drug designation is granted by the FDA Office of Orphan Products Development to investigational treatments that are intended for the treatment of rare diseases affecting fewer than 200,000 people in the United States. The program was developed to encourage the development of medicines for rare diseases, and benefits include tax credits and application fee waivers designed to offset some development costs, as well as eligibility for market exclusivity for seven years post approval.

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.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as anticipates, believes, expects, intends, projects, and future or similar expressions are intended to identify forward-looking statements. Forward-looking statements include statements concerning or implying the potential of our product candidates, including TSHA-105, to positively impact quality of life and alter the course of disease in the patients we seek to treat, our research, development and regulatory plans for our product candidates, the potential benefits of rare pediatric disease designation and orphan drug designation to our product candidates, the potential for these product candidates to receive regulatory approval from the FDA or equivalent foreign regulatory agencies, and whether, if approved, these product candidates will be successfully distributed and marketed. Forward-looking statements are based on managements current expectations and are subject to various risks and uncertainties that could cause actual results to differ materially and adversely from those expressed or implied by such forward-looking statements. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. Risks regarding our business are described in detail in our Securities and Exchange Commission (SEC) filings, including in our Quarterly Report on Form 10-Q for the quarter ended September 30, 2020, which is available on the SECs website at http://www.sec.gov. Additional information will be made available in other filings that we make from time to time with the SEC. Such risks may be amplified by the impacts of the COVID-19 pandemic. These forward-looking statements speak only as of the date hereof, and we disclaim any obligation to update these statements except as may be required by law.

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Taysha Gene Therapies Receives Rare Pediatric Disease and Orphan Drug Designations for TSHA-105 for the Treatment of Epilepsy Caused by SLC13A5...

New York, Jan. 19, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Cancer Gene Therapy Market 2021-2025" - https://www.reportlinker.com/p05060878/?utm_source=GNW Our report on cancer gene therapy market provides a holistic analysis, market size and forecast, trends, growth drivers, and challenges, as well as vendor analysis covering around 25 vendors. The report offers an up-to-date analysis regarding the current global market scenario, latest trends and drivers, and the overall market environment. The market is driven by the side effects of traditional cancer treatments, benefits associated with gene therapy for cancer treatment and the rising prevalence rate of cancer boosting the demand for cancer therapeutics. In addition, the side effects of traditional cancer treatments is anticipated to boost the growth of the market as well. The cancer gene therapy market analysis includes application segments and geographical landscapes.

The cancer gene therapy market is segmented as below: By Application Oncolytic virotherapy Gene transfer Gene-induced immunotherapy

By Geographical Landscapes North America Europe Asia ROW

This study identifies the rising partnerships and collaborations as one of the prime reasons driving the cancer gene therapy market growth during the next few years. Also, favorable government regulations for gene therapy programs and rapid growth potential in developing economies will lead to sizable demand in the market.

The analyst 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. Our report on cancer gene therapy market covers the following areas: Cancer gene therapy market sizing Cancer gene therapy market forecast Cancer gene therapy market industry analysis

Read the full report: https://www.reportlinker.com/p05060878/?utm_source=GNW

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The Global Cancer Gene Therapy Market is expected to grow by $ 2.96 bn during 2021-2025 progressing at a CAGR of 20% during the forecast period -...

Gene Therapy Technologies Market Report recently published by Worldwide Market Reports company focuses mostly on required solutions to the users. The study includes analysis, forecast, and revenue from 2021 to 2026. The advancement rate is evaluated dependent on insightful examination that gives credible information on the worldwide market. Imperatives and advancement points are merged together after a significant comprehension of the improvement of this market.

There is Continuous growth in the Gene Therapy Technologies Market in the last five years and also continued for the forecasted period. Gene Therapy Technologies industry report analyses the outline of the global market with respect to major regions and segmented by types and applications. This report covers top manufacturers, product scope, market overview, market opportunities, market risk, market driving force, technological advancement, distributors, traders, dealers, research findings.

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The top players covered in Gene Therapy Technologies Market are: Bluebird bio, Adaptimmune, GlaxoSmithKline, Merck, Celgene, Shanghai Sunway Biotech, BioCancell, Shenzhen SiBiono GeneTech, SynerGene Therapeutics, OncoGenex Pharmaceuticals, Genelux Corporation, Cell Genesys, Advantagene, GenVec, BioCancell, Celgene, Epeius Biotechnologies, Introgen Therapeutics, Ziopharm Oncology

The point-to-point elucidation of the markets assembling system, the usage of advancement, conclusions of the world market players, dealers and suppliers order, and the explicit business data and their improvement plans would help our customers for future courses of action and movement planned to make due in the Gene Therapy Technologies market.

The data always remains relevant to the market and consists of market dynamics, prospects, starts, market dynamics, and even the Global market volumes into account. It filled with data and deep analysis on market value, environmental analysis, Gene Therapy Technologies advanced techniques, latest developments, Gene Therapy Technologies business strategies, and current trends. Hence, it becomes a valuable asset to both manufacturers and investors of the industry.

Points Covered of this Gene Therapy Technologies Market report are:

The international Gene Therapy Technologies market has been characterized by several primary factors, with each factor tends to play a crucial role in the boom of the market. The growth in the products has doubled with the smoother availability of the customer base that has been helping the company flourishing globally. On the other hand, the presence of a dynamic supply chain has helped the company to grow exponentially.

The analysis and forecast of the global market of Gene Therapy Technologies have no longer been, specifically, analyzed that are not only on a global foundation but additionally on a neighborhood foundation. When a better look taken at the areas, the market has concentrated, and the file interior the important makes a strong point of Europe, Middle East & Africa, Asia Pacific, Latin America, and North America. These areas have studied regarding the hooked-up traits and the diverse possibilities in addition to the outlook that allows inside the benefitting of the market ultimately.

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Research Methodology:

The Gene Therapy Technologies market report has been prepared after thorough market research being conducted. It has been prepared as per Porters Five Force Model. In terms of timeline, the market takes the period between 2021-2026 into account for assessment. Apart from this, a comprehensive SWOT analysis has been provided for swift business decision making.

Enumerating some of the fundamental parameters encompassed in the report:

Global Gene Therapy Technologies Market Report includes Detailed TOC points:

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Gene Therapy Technologies Market Estimated to Experience a Hike in Growth by 2021 2026: Bluebird bio, Adaptimmune, GlaxoSmithKline - KSU | The...

Drugs that target the cancer-promoting proteins MDM2 and BET have been tried in acute myeloid leukemia (AML) and haven't been all that effective on their own. But what if they were combined?

Researchers at the Sanford Burnham Prebys Medical Discovery Institute and the University of Glasgow have early evidence a combination strategy may, in fact, work in AML.

Combining MDM2 and BET inhibitors improved the killing of AML cell lines in lab studies and was more effective than solo treatment in eradicating the cancer in mouse models, the researchers reported in the journal Nature Communications. The combination seems to work by activating the tumor-suppressing protein p53, they reported.

The results were surprising because previous research had shown that each drug on its own had modest benefit against AML, said senior author Peter Adams, Ph.D., a professor at Sanford Burnham Prebys, in a statement. The new research provides scientific rationale to advance clinical studies of the drug combination in patients with AML.

The gene TP53 produces the protein p53, a known tumor suppressor. TP53 is frequently mutated across a range of cancers, which is why targeting the gene is a popular pursuit in oncology research.

Until now, the popular thinking was that MDM2 inhibitors activate p53. BET inhibitors, on the other hand, suppress leukemia-associated genes but dont affect p53, researchers believed.

Adams and his team tested MDM2 and BET inhibitors in AML cell lines and samples from patients. They were surprised to discover that BET inhibitors actually do activate p53by suppressing another protein called BRD4. Combining MDM2 and BET inhibition produces a 'double whammy' effect that fully unleashes the anti-cancer activity of p53, Adams said.

RELATED: How novel combos could overcome resistance to targeted drugs in leukemia, solid tumors and more

The Sanford Burnham Prebys-led team went on to test the combination in two mouse models of AML. In both cases, inhibiting BET and MDM2 together outperformed either mechanism on its own in eradicating the cancer and extending survival, the researchers reported.

The biopharma industry continues to show an interest in both BET and MDM2 inhibitors, though development efforts have run into some obstacles.

In 2019, Roche dropped a phase 1 BET inhibitor from its pipeline. And last April, the Swiss pharma giant stopped testing MDM2 inhibitor idasanutlin in a phase 3 AML trial after a combination of the drug with cytarabine proved disappointing. Early trials of idasanutlin in combination with Roches AML drug Venclexta are underway.

Meanwhile, other early-stage BET and MDM2 inhibitors have driven some deal-making in biopharma. In 2018, Aptose Biosciences teamed up with Ohm Oncology to advance a BET inhibitor in hematologic cancers. And last September, Rain Therapeutics licensed an MDM2-targeted drug from Daiichi Sankyo and raised $63 million to take it into pivotal trials in differentiated or dedifferentiated liposarcoma.

The Sanford Burnham Prebys and University of Glasgow researchers noted in their study that the heterogeneity of AML makes it a particularly difficult disease to address with targeted treatments. While many different genes can be mutated to drive the disease, no single mutation is dominant in a majority of patients.

But 90% of AML tumors have TP53, suggesting that human AML subtypes employ alternative mechanisms to inactivate the p53 pathway.

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Unleashing the cancer-fighting gene TP53 in leukemia with a novel combination treatment - FierceBiotech

Rising Demand for Gene Therapy Market 2021

Gene Therapy Market analysis on global market is a thorough study that offers a select combination of skillful market realities. The study shows changing market trends as well as the size of individual segments in this market. This report mentions various top players involved in this market. Analysis of the Global Gene Therapy Market begins with a market-based outline and underlines the current information on the global market, complemented by data on the current situation.

Global Gene Therapy Market report is a comprehensive study of the global market and has been recently added by Market Research Inc to its extensive database. Augmented demand for the global market has been increased in the last few years. This informative research report has been scrutinized by using primary and secondary research. The Global Gene Therapy Market is a valuable source of reliable data including data of the current market.

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Top Key Players Profiled in This Report

Novartis AG, Gilead Sciences, Inc., UniQure N.V., Spark Therapeutics LLC, Bluebird Bio, Juno Therapeutics, GlaxoSmithKline PLC, Celgene Corporation, Shire PLC,

The key questions answered in the report:

Across the globe, different regions such as North America, Latin America, Asia-Pacific, Europe, and Africa have been examined on the basis of productivity and manufacturing base. Researchers of this report throw light on different terminologies of the Global Gene Therapy Market.

This research report represents a 360-degree overview of the competitive landscape of the Global Gene Therapy Market. Furthermore, it offers massive data relating to the recent trends, technological advancements, tools, and methodologies. The research report analyzes the Global Gene Therapy Market in a detailed and concise manner for better insights into the businesses.

The research study has taken the help of graphical presentation techniques such as info graphics, charts, tables, and pictures. It provides guidelines for both established players and new entrants in the Global Gene Therapy Market.

The detailed elaboration of the Global Gene Therapy Market has been provided by applying industry analysis techniques such as SWOT and Porters five-technique. Collectively, this research report offers a reliable evaluation of the global market to present the overall framework of businesses.

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Table of Contents:

This report provides pin-point analysis for changing competitive dynamics

It provides a forward looking perspective on different factors driving or restraining market growth

It provides a six-year forecast assessed on the basis of how the market is predicted to grow

It helps in understanding the key product segments and their future

It provides pin point analysis of changing competition dynamics and keeps you ahead of competitors

It helps in making informed business decisions by having complete insights of market and by making in-depth analysis of market segments

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Big Boom in Gene Therapy Market Detailed Analysis of Current and Future Industry Figures till 2028 |Novartis AG, Gilead Sciences, Inc., UniQure N.V.,...