Posts Tagged ‘medicine’

NINA MOINI: The Minneapolis Saint Paul International Film Festival is currently under way. And tonight, a documentary will premiere called "Sequencing Hope." The film is directed by Lindsey Seavert and Maribeth Romslo. It follows an Alabama family who came to Minnesota to get their young daughter life-saving gene therapy for a rare disease. Let's listen to a clip from the trailer.

CELIA GRACE HAMLETT: Can you hold my hand?

[CHUCKLES]

They give me the medicine.

SUBJECT 1: There is lots of other gene therapy research on the horizon.

SUBJECT 2: That's got far-reaching consequences to move medicine forward.

SUBJECT 3: In my heart, I feel that the good Lord has something in store for Celia Grace.

SUBJECT 4: We just pray, Lord, for a miracle. We pray for a healing for Celia Grace.

SUBJECT 5: You know, when it comes to your kids, you're going to do whatever it takes to protect them.

SUBJECT 6: If it saves one child, then I feel like we have accomplished something.

NINA MOINI: Celia Grace Hamlett was four-years-old when she came to M Health Fairview Masonic Children's Hospital in 2021 and became the first person in the US to undergo the experimental gene therapy. Her family's in town for the film's premiere tonight and Celia Grace's dad, Gary, joins us now along with their doctor, Doctor Paul Orchard. Thank you both for being here.

GARY HAMLETT: Thank you.

PAUL ORCHARD: Thank you, Nina.

NINA MOINI: Yeah, and Gary, let me start with you if I might. Tell us about your daughter, Celia Grace. She's seven-years-old now and I understand she was diagnosed with this rare and often fatal genetic disorder, MLD, when she was diagnosed at three-years-old. What were her options at that point?

GARY HAMLETT: Well, at that point had one or had two options. One was bone marrow transplant or the other was gene therapy that was only being done in Milan, Italy.

NINA MOINI: Wow. Doctor Orchard, can you tell us all what MLD is?

PAUL ORCHARD: Certainly. Appreciate the opportunity to speak with you today. So metachromatic leukodystrophy is a rare inherited disorder. It's what we call a lysosomal disease. The lysosome is an organelle within cells that help break down materials that the cell is attempting to get rid of.

And there's a number of enzymes that are present in the lysosome that help accomplish that. Arylsulfatase A. is one of those. And in this circumstance, if you are unlucky enough to receive a mutation within the arylsulfatase gene from both mom and from dad, then you're affected with the disease.

But both parents who have one normal copy of the gene are absolutely fine. There's nothing to suggest that they have any sort of problem, but again, if you receive an abnormal copy from both parents then you see the disease. And in this situation, it's primarily a neurologic disorder. It occurs in kids as young as one or so in terms of manifestations of the disease, but it's progressive and lethal if there's no therapy.

NINA MOINI: Wow, that's just so much to take in, Gary. And you know, you mentioned having to maybe think about treatment over in Milan. How did you hear about the treatment for MLD that was right here in Minnesota?

GARY HAMLETT: Our doctor neurologist in Alabama, Doctor Matt, is the one that contacted us and said, what would y'all think if I told y'all y'all's daughter was going to make history books? At that point we said, what do you mean? And she said, well, your daughter may be the first child in the United States to receive gene therapy for MLD and it will be done at the Masonic Children's Hospital in Minneapolis under the care of Doctor Paul Orchard.

NINA MOINI: And then what did you think? I mean, were you going to have to pay for that?

GARY HAMLETT: Yes. At that point we didn't really care what it cost us being able to save our daughter's life. So our community started doing fundraisers to try to raise money to pay for this.

NINA MOINI: Wow, yeah. Doctor Orchard, can you explain how the gene therapy works and is it accessible to most people or is it just too costly?

PAUL ORCHARD: Well, the gene therapy clinical trials occurred in Europe, as Gary was alluding to, and the data was sufficiently positive that it was approved as therapy in the EU, essentially. So it's been licensed therapy there for several years, but none of the clinical trials have been done here in the US.

And because of the promise of this new therapy, we were gearing up to being able to offer this regardless, but there was the opportunity in this situation from Celia Grace's diagnosis to be able to intervene. So it's just become licensed therapy in the last month or so, as March 18th.

But prior to that and for Celia Grace, we had to petition the FDA to allow us to use it because it's still considered experimental therapy, and get all the approvals from all the various regulatory groups to be able to do that. So it took some time, but it opened the doors. And now we've treated a total of five patients with compassionate use therapy.

NINA MOINI: All right. Is it still pretty pricey, though? I understand it's among some of the priciest treatments.

PAUL ORCHARD: Yes, it is very expensive. So for the compassionate use treatment as an experimental therapy, the company actually donated the cell product, but it's millions of dollars now as licensed therapy.

NINA MOINI: Yeah. So still working to make it more accessible. Gary, you said something that really struck me in the trailer for the film. You said that you take care of people for a living. I understand you work in law enforcement, but you couldn't fix this for your daughter. And it seems like this film is really an exploration of your family's journey. Tell me how did that feel to feel sort of helpless in the moment, but then to see her go through this journey and be, I mean, cured?

GARY HAMLETT: We just felt very helpless, not knowing the outcome of it, how sick Grace was. Just thinking that we were going to lose our daughter. Possibly by the age of five-years-old.

NINA MOINI: Yeah.

GARY HAMLETT: And seeing her now as a normal seven-year-old, running, playing, is going to graduate in kindergarten, and it's just an amazing feeling.

NINA MOINI: Yeah, I'm sure. And so how is she doing? Tell us a little bit just about how she's getting around fine, and she's feeling well.

GARY HAMLETT: Oh, she is rambunctious, non-stop playing, running, doing her schoolwork. She is just like a typical seven-year-old little girl.

NINA MOINI: Yeah, and I understand some more patients are going to be undergoing that same treatment as Celia Grace, which is great news, Doctor Orchard.

PAUL ORCHARD: Yes, I hope it's going to be widely available. As you mentioned, the cost is going to be significant and attempting to determine how we're going to do this. The vast majority of these patients that we treat are obviously not from Minnesota.

And so being able to get insurance that's going to work across state lines and going to be sufficient for this is going to be a challenge. But that's one of the things that we're currently working on.

NINA MOINI: OK, and Gary, I'll leave the last question for you here. What do you hope people will take away from watching your family's story in this documentary?

GARY HAMLETT: The struggles of not knowing the outcome of your child. The struggles of possibly knowing that you will only have a few years with your child. And then knowing that there are people out there willing to help and willing to do anything possible to save your daughter or your son. I just can never repay everybody that along this journey for what they have done for my child.

NINA MOINI: Yeah, and it really sounds like it's some of the best parts of humanity and also some of the hardest struggles that anyone will go through. Thank you so much for sharing that journey and for being here, Gary. And to you as well, Doctor Orchard, thank you, and congratulations on this film reaching an audience today.

PAUL ORCHARD: Thank you.

GARY HAMLETT: Thank you so much.

NINA MOINI: Gary Hamlett is the father of Celia Grace Hamlett and Doctor Orchard is a pediatric blood and marrow transplant physician at M. Health Fairview. Both are featured in the documentary, "Sequencing Hope," which is premiering tonight at 7:00 PM. We'll have that information on our website, mprnews.org.

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Genetically engineered B cells could produce super-antibodies to HIV

Researchers at Washington University School of Medicine in St. Louis have received a $6.2 million grant from the National Institutes of Health (NIH) to develop a gene therapy that would modify the immune systems B cells to spur them to produce broadly neutralizing antibodies against HIV. In theory, such an approach could control or eliminate the infection without need for ongoing antiretroviral therapy. Shown is the engineered adenovirus designed to deliver HIV superantibody genes into B cells.

HIV infections can be controlled with medication, but such therapy must continue throughout patients lives because no strategy exists to eliminate the virus from the body or control the infection without ongoing treatment.

With the aim of developing such a strategy, researchers at Washington University School of Medicine in St. Louis have received a $6.2 million grant from the National Institutes of Health (NIH) to develop a gene therapy that would modify the immune systems B cells to spur them to produce broadly neutralizing antibodies against HIV. In theory, such an approach could control or eliminate the infection without need for ongoing antiretroviral therapy.

Permanent ways to control or eliminate HIV infection remain elusive, and their development is a major goal of the field, said David T. Curiel, MD, PhD, the Distinguished Professor of Radiation Oncology. The idea of modifying B cells which naturally produce antibodies to ensure that they manufacture specific antibodies that are broadly effective at targeting HIV is an exciting strategy. We have brought together a great team with expertise in HIV, gene therapy, and animal models of infection to work toward this goal.

Curiels co-principal investigators are Michael R. Farzan, PhD, of Harvard Medical School and Boston Childrens Hospital, and Mauricio de Aguiar Martins, PhD, of the University of Florida.

Over the decades since HIV appeared, researchers have learned that about 1% of people with the virus are able to produce what might be considered superantibodies against the virus. Such individuals known as elite neutralizers can produce antibodies against multiple strains of HIV.

Some people naturally have antibodies that can bind and destroy or deactivate very diverse strains of HIV, and we now have the ability to build those types of antibodies in the lab, said Paul Boucher, a doctoral student in Curiels lab. But just giving other patients these superantibodies is not an ideal solution, because these proteins would stay in the body only temporarily. Instead, our approach is to genetically modify the cells responsible for making antibodies the immune systems B cells so they can always produce superantibodies against HIV whenever they may need to.

Such engineered B cells could create, in theory, a state of permanent vaccination against the virus. Even if such a gene therapy doesnt fully clear HIV from the body, the strategy could allow the amount of virus in the body to be controlled, keeping it at a minimal level and creating a functional cure, according to the researchers.

The strategy involves modifying a different type of virus, called adenovirus. When used in gene therapy, such viruses are genetically disabled so they cant cause disease. The researchers then could engineer the adenovirus to carry the gene responsible for manufacturing broadly neutralizing antibodies to HIV. In the same viral vector, they also could include genes responsible for manufacturing the CRISPR/Cas9 gene editing proteins. In this way, the gene therapy delivery vehicle would carry into the body both the antibody gene that will be edited into the B cell genome and the genes to build the molecular tools to carry out that editing.

Using a three-part targeting strategy, the researchers would design the adenovirus to deliver its genetic payload only to B cells, avoiding other cell types. They have developed ways to modify the virus so that it is targeted directly to a protein that is expressed on the surface of B cells and no other cell types. The researchers can further restrict the targeting by using genetic methods to ensure that the CRISPR/Cas9 proteins can only be manufactured when their genes are delivered into B cells. Finally, they have developed strategies to modify the adenovirus in a way that stops its natural tendency to accumulate in the liver.

This strategy to modify B cells is distinct from another adenoviral gene therapy approach to HIV treatment that is currently in clinical trials led by principal investigator Rachel M. Presti, MD, PhD, a professor of medicine in the Division of Infectious Diseases at Washington University School of Medicine. HIV is difficult to eliminate from the body because the virus integrates its genome into the DNA of the infected individuals T cells. The strategy currently in clinical trials is focused on using precise targeting of the CRISPR/Cas9 gene editing proteins to excise the virus from the genomes of all of a patients infected T cells. This strategy is being tested in a first-in-human, phase 1 clinical trial to determine its safety and preliminary efficacy at various doses.

Curiel said engineered B cells are ripe for developing new therapies to treat a wide variety of diseases. In November, a genetically engineered B cell therapy was administered to a patient for the first time at the University of Minnesota Medical Center. In that case, the therapy was designed to treat mucopolysaccharidosis type 1, a life-threatening condition in which the body lacks an enzyme necessary to break down large sugar molecules inside cells.

Gene therapy with engineered B cells is an exciting new area of research, Curiel said. We look forward to combining our expertise in adenovirus gene therapy, HIV infection and preclinical models of disease to realize our plan for developing an HIV therapy that we hope can permanently control the infection.

This work is supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), grant number 1R01-AI174270-01A1. This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

About Washington University School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,900 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has grown 56% in the last seven years. Together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,900 faculty physicians practicing at 130 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Childrens hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

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$6.2 million to help develop gene therapy for HIV Washington University School of Medicine in St. Louis - Washington University School of Medicine in...

Kelly Banas, Ph.D., principal investigator at ChristianaCares Gene Editing Institute, will present her latest research discovery related to targeting the NRF2 gene in cancer cells at the first CRISPR Medicine Conference held in Copenhagen, Denmark, April 22 to 25. The Gene Editing Institutes research has focused on the NRF2 gene and the strong immune response []

The post Kelly Banas, Ph.D., To Present Her Latest Discovery at CRISPR Medicines First International Conference appeared first on ChristianaCare News.

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Kelly Banas, Ph.D., To Present Her Latest Discovery at CRISPR Medicine's First International Conference - Milford LIVE

Overview

The human body regenerates itself constantly, replacing old, worn-out cells with a continuous supply of new ones in almost all tissues. The secret to this perpetual renewal is a small but persistent supply of stem cells, which multiply to replace themselves and also generate progeny that can differentiate into more specialized cell types. For decades, scientists have tried to isolate and modify stem cells to treat disease, but in recent years the field has accelerated dramatically.

A major breakthrough came in the early 21st century, when researchers in Japan figured out how to reverse the differentiation process, allowing them to derive induced pluripotent stem (iPS) cells from fully differentiated cells. Since then, iPS cells have become a cornerstone of regenerative medicine. Researchers can isolate cells from a patient, produce iPS cells, genetically modify them to repair any defects, then induce the cells to form the tissue the patient needs regenerated.

On April 26, 2019, the New York Academy of Sciences and Takeda Pharmaceuticals hosted the Frontiers in Regenerative Medicine Symposium to celebrate 2019 Innovators in Science Award winners and highlight the work of researchers pioneering techniques in regenerative medicine. Presentations and an interactive panel session covered exciting basic research findings and impressive clinical successes, revealing the immense potential of this rapidly developing field.

Shinya Yamanaka Kyoto University

Shruti Naik New York University

Michele De Luca University of Modena and Reggio Emilia

Masayo Takahashi RIKEN Center for Biosystems Dynamics Research

Hiromitsu Nakauchi Stanford University and University of Tokyo

Brigid L.M. Hogan Duke University School of Medicine

Emmanuelle Passegu Columbia University Irving Medical Center

Hans Schler Max Planck Institute for Molecular Biomedicine

Austin Smith University of Cambridge

Moderator: Azim Surani University of Cambridge

Shinya Yamanaka Kyoto University

Shinya Yamanakaof Kyoto University, gave the meetings keynote presentation, summarizing his laboratorys recent work using induced pluripotent stem (iPS) cells for regenerative medicine. The first clinical trial using iPS cells to treat age-related macular degeneration started five years ago. In his clinical trial, physicians isolated somatic cells from a patient, then used developed culture techniques to derive iPS cells from them. iPS cells can proliferate and differentiate into any type of cell in the body, which can then be transplanted back into the patient. Experiments over the past five years have shown that this approach has the potential to treat diseases ranging from age-related macular degeneration to Parkinsons disease.

However, this autologous transplantation strategy is slow and expensive. It takes up to a year just evaluating one patient, [and] it costs us almost one million US dollars, said Yamanaka. Before transplanting the differentiated cells, the researchers evaluated the entire iPS cell derivation and iPS cell differentiation processes, adding to time and cost. As another strategy, Yamanakas team is working on the iPS Cell Stock for Regenerative Medicine. Here, iPS cells are derived from blood cells of healthy donors, not the patients, and are stocked. The primary problem with this approach is the human leukocyte antigen (HLA) system, which encodes multiple cell surface proteins. Each person has a specific combination of HLA genes, or haplotype, defining the HLA proteins expressed on their own cells. The immune system recognizes and eliminates any cell expressing non-self HLA proteins. Because there are millions of potential HLA haplotypes, cells derived from one person will likely be rejected by another.

The homozygous superdonor cell line has limited immunological diversity, allowing it to match multiple patients.

To address that, Yamanaka and his colleagues are collaborating with the Japanese Red Cross to develop superdonor iPS cells. These cells carry homozygous alleles for different human lymphocyte antigen (HLA) genes, limiting their immunological diversity and making them match multiple patients. So far, the team has created four superdonor cell lines, allowing them to generate cells compatible with 40% of the Japanese population. Those cells are now being used in clinical trials treating macular degeneration and Parkinsons disease, with more indications planned.

So far so good, said Yamanaka, but he added that in order to cover 90% of the Japanese population we would need 150 iPS cell lines, and in order to cover the entire world we would need over 1,000 lines. It took the group about five years to generate the first four lines, so simply repeating the process that many more times isnt practical.

Instead, Yamanaka hopes to take the HLA reduction a step further, knocking out most of the major HLA genes to generate cells that will survive in large swaths of the population. However, simply knocking out entire families of genes isnt enough. Natural killer cells attack cells that are missing particular cell surface antigens, so the researchers had to leave specific markers in the cells, or reintroduce them transgenically. Natural killer and T cells from various donors ignore leukocytes derived from these highly engineered iPS cells, proving that the concept works. With this approach, just ten lines of iPS cells should yield a range of donor cells suitable for any human HLA combination. Yamanaka expects these gene-edited iPS cells to be available in 2020.

By 2025, Yamanaka hopes to announce my iPS cell technology. This technology will reduce the cost and time for autologous transplantation to about $10,000 and one month per patient.

While preclinical and early clinical trials on iPS cells have yielded promising results, the new therapies must still cross the valley of death, the pharmaceutical industrys term for the unsuccessful transition and industrialization of innovative ideas identified in academia to routine clinical use. In an effort to make that process more reliable, Yamanaka and his colleagues have begun a unique collaboration with Takeda Pharmaceutical Company Limited, Japans largest drug maker. The effort involves 100 scientists, 50 each from the company and academic laboratories. The corporate researchers gain access to the latest basic science developments on iPS cell technology, while the academics can use the companys cutting-edge R&D know-how equipment and vast chemical libraries.

In one project, the collaborators used iPS cells to derive pancreatic islet cells, and then encapsulated the cells in an implantable device to treat type 1 diabetes. The system successfully decreased blood glucose in a mouse model, and the team is now scaling up cell production to test it in humans in the future. Another effort identified chemicals in Takedas compound library that speed cardiomyocyte maturation, which the researchers are now using to improve iPS cell-derived treatments for heart failure. In a third project, the team has modified iPS cell-derived T cells to identify and attack tumors, again showing promising results in a mouse model.

Shruti Naik New York University

Michele De Luca University of Modena and Reggio Emilia

Shruti Naik, Early-Career Scientist winner of the 2019 Innovators in Science Award, discussed her work on epithelial barriers. These barriers, which include skin and the linings of the gut, lungs, and urogenital tract, exhibit nuanced responses to the many microbes they encounter. Injuries and pathogenic infections trigger prompt inflammatory responses, but the millions of harmless commensal bacteria that live on these surfaces dont. How does the epithelium know the difference?

To ask that question, Naik first studied germ-free mice, which lack all types of bacteria. These animals have defective immune responses against pathogens that affect epithelia, so commensal bacteria are clearly required for developing normal epithelial immunity. Naik inoculated the germ-free mice with bacterial strains found either on the skin or in the guts of normal mice, then assessed their immune responses in those two compartments.

When you gave gut-tropic bacteria, you were essentially able to rescue immunity in the gut but not the skin, and conversely when you gave skin-tropic bacteria, you were able to rescue immunity in the skin and not the gut, said Naik. Even though the commensal bacteria caused no inflammation, they did activate certain T cells in the epithelia they colonized, apparently preparing those tissues for subsequent attacks by pathogens.

Next, Naik took germ-free mice inoculated with Staphylococcus epidermidis, a normal skin commensal bacterium, and challenged them with an infection by Candida albicans, a pathogenic yeast. The bacterially primed mice produced a much more robust immune response against the yeast infection than control animals that hadnt gotten S. epidermidis. Naik confirmed that this immune training effect operates through the T cell response shed seen before. You essentially develop an immune arsenal to your commensals that helps protect against pathogens, Naik explained, adding that each epithelial barrier requires its own commensal bacteria to trigger this response.

Augmented wound repair in post-inflammation skin reveals that naive and inflammation-educated skin stem cells respond differently to subsequent stresses.

The response to epithelial commensals is remarkably durable; Naik found that the skin T cells in the inoculated mice remained on alert a year after their initial activation. That led her to wonder whether non-hematopoietic cells, especially epithelial stem cells, contribute to immunological memory in the skin.

To probe that, Naik and a colleague used a mouse model in which the topical drug imiquimod induces a temporary psoriasis-like skin inflammation. By tracing the lineages of cells in the animals skin, the researchers found that epithelial stem cells expand during this inflammation, and then persist. Challenging the mice with a wound one month after the inflammation resolves leads to faster healing than if the mice hadnt had the inflammation. Several other models of wound healing yielded the same result. The investigators concluded that naive and inflammation-educated skin stem cells respond differently to subsequent stresses.

Naiks team found that inflammation causes persistent changes in skin stem cells chromatin organization. Using a clever reporter gene assay, they demonstrated that the initial inflammation leaves inflammatory gene loci more open in the chromatin, making them easier to activate after subsequent insults. What was really surprising to us was that this change never fully resolved, said Naik. Even six months after the acute inflammation, skin stem cells retained the distinct post-inflammatory chromatin structure and the ability to heal wounds quickly. This chronic ready-for-action state isnt always beneficial, though. Naik noticed that the mice that had had the inflammatory treatment were more prone to developing tumors, for example.

In establishing her new laboratory, Naik has now turned her focus to another aspect of epithelial immunity: the link between immune responses and tissue regeneration. She looked first at a type of T cells found in abundance around hair follicles on skin. Mice lacking these cells exhibit severe delays in wound healing, apparently as a result of failing to vascularize the wound area. That implies a previously unknown role for inflammatory T cells in vascularization, which Naik and her lab are now probing.

Michele De Luca, Senior Scientist winner of the 2019 Innovators in Science Award, has developed techniques for regenerating human skin from transgenic epidermal stem cells. Researchers first isolated holoclones, or cells derived from a single epidermal stem cell, over 30 years ago. These cells can be used to grow sheets of skin in culture for both research and clinical use, but scientists have only recently begun to elucidate how the process works.

The first stem cell-derived therapies tested in humans were for skin and eye burns, allowing doctors to regenerate and replace burned epidermal tissue from a patients own stem cells. Thats the basis of Holoclar, a stem cell-based treatment for severe eye burns approved in Europe in 2015.

Holoclar and similar procedures work well for injured patients with normal epithelia. We wanted to genetically modify those cells in order to address one of the most important genetic diseases in the dermatology field, which is epidermolysis bullosa (EB), a devastating skin disease, said De Luca. In EB, patients carry a genetic defect in cell adhesion that causes severe blisters all over their skin and prevents normal healing. A large number of EB patients die as children from the resulting infections, and those who survive seldom get beyond young adulthood before succumbing to squamous cell carcinomas.

De Luca developed a strategy to isolate stem cells from a skin biopsy, repair the genetic defect in these cells with a retroviral vector, and then grow new skin in culture that can be transplanted back to the patient, replacing their original skin with genetically repaired skin. In 2015, the researchers carried out the procedure on a young boy named Hassan, who had arrived in the burn unit of a German hospital with EB after fleeing Syria. The burn unit was only able to offer palliative care, and his prognosis was poor because of his constant blistering and infections. De Lucas team received approval to perform their gene therapy on him.

The new strategy, which combines cell and gene therapy, resulted in the restoration of normal skin adhesion in Hassan.

After isolating and modifying epidermal stem cells from Hassan and growing new sheets of skin in culture, De Lucas team re-skinned the patients arms and legs, then his abdomen and back. The complete procedure took about three months. The new skin resists blister formation even when rubbed and heals normally from minor wounds. In the ensuing three and a half years, Hassan has begun growing normally and living an ordinary, healthy life.

Detailed analysis of skin biopsies showed that Hassans epidermis has normal cellular adhesion machinery and revealed that his skin is now derived from a population of proliferating transgenic stem cells, with no single clone dominating. By tracing the lineages of cells carrying the introduced transgene, De Luca was able to identify self-renewing transgenic stem cells, intermediate progenitor cells, and fully differentiated stem cells, indicating normal skin growth and replacement.

Besides being good news for the patient, the results confirmed a longstanding theory of skin regeneration. These data formally prove that the human epidermis is sustained only by a small population of long-lived stem cells that generates [short-lived epithelial] progenitors, said De Luca, adding that with this in mind, weve started doing other clinical trials.

The researchers plan to continue targeting junctional as well as dystrophic forms of EB, both of which are genetically distinct from EB simplex. Initial experiments revealed that in these conditions, transplant recipients developed mosaic skin, where some areas continued to be produced from cells lacking the introduced genetic repair. The non-transgenic cells appeared to be out-competing the transgenic cells and supplanting them, undermining the treatment. De Luca and his colleagues developed a modified strategy that gave the transgenic cells a competitive advantage. This approach and additional advances should allow them to achieve complete transgenic skin coverage.

Masayo Takahashi RIKEN Center for Biosystems Dynamics Research

Hiromitsu Nakauchi Stanford University and University of Tokyo

Masayo Takahashi, of RIKEN Center for Biosystems Dynamics Research, began her talk with a brief description of the new Kobe Eye Center, a purpose-built facility designed to house a complete clinical development pipeline dedicated to curing eye diseases. Not only cells, not only treatments, but a whole care system is needed to cure the patients, said Takahashi. In keeping with that philosophy, the Center includes everything from research laboratories to a working eye hospital and a patient welfare facility.

Takahashis recent work has focused on treating age-related macular degeneration (AMD). In AMD, the retinal pigment epithelium that nourishes other retinal cells accumulates damage, leading to progressive vision loss. AMD is the most common cause of serious visual impairment in the elderly in the US and EU, and there is no definitive treatment. Fifteen years ago, Takahashi and her colleagues derived retinal pigment epithelial cells from monkey embryonic stem cells and successfully transplanted them into a rat model of AMD, treating the condition in the rodents. They were hesitant to extend the technique to humans, though, because it required suppressing the recipients immune response to prevent them from rejecting the monkey cells.

The advent of induced pluripotent stem (iPS) cell technology pointed Takahashi toward a new strategy, in which she took cells from a patient, derived iPS cells from them, and then prompted those cells to differentiate into retinal pigment epithelial cells that were perfectly compatible with the patients immune system. Her team then transplanted a sheet of these cells into the patient. That experiment, in 2014, was the first clinical use of iPS cells in humans. The grafted cells were very stable, said Takahashi, who has checked the graft in multiple ways in the ensuing years.

Having proven that iPS cell-derived retinal grafts can work, Takahashi and her colleagues sought to make the procedure cheaper and faster. Creating customized iPS cells from each patient is a huge undertaking, so instead the team investigated superdonor iPS cells that can be used for multiple patients. These cells, described by Shinya Yamanaka in his keynote address, express fewer types of human leukocyte antigens than most patients, making them immunologically compatible with large swaths of the population. Just four lines of superdonor iPS cells can be used to derive grafts for 40% of all Japanese people.

Transplantation of an iPS cell-derived sheet into the retina ultimately proved successful.

In the next clinical trial, Takahashis lab performed several tests to confirm that the patients immune cells would not react with the superdonor cells, before proceeding with the first retinal pigment epithelial graft. Nonetheless, after the graft the researchers saw a minuscule fluid pocket in the patients retina, apparently due to an immune reaction. Clinicians immediately gave the patient topical steroids in the eye to suppress the reaction. Then after three weeks or so, the reaction ceased and the fluid was gone, so we could control the immune reaction to the HLA-matched cells, said Takahashi. Four subsequent patients showed no reaction whatsoever to the iPS superdonor-derived grafts.

While the retinal grafts were successful, none of the patients have shown much improvement in visual acuity so far. Takahashi explained that subjects in the clinical trial all had very severe AMD and extensive loss of their eyes photoreceptors. I think if we select the right patients, we could get good visual acuity if their photoreceptors still remain, said Takahashi.

Takahashi finished with a brief overview of her other projects, including using aggregates of iPS cells and embryonic stem cells to form organoids, which can self-organize into a retina. She hopes to use this system to develop new therapies for retinitis pigmentosa, another major cause of vision loss. Finally, Takahashi described a project aimed at reducing the cost and increasing the efficacy of stem cell therapies even further by employing a sophisticated laboratory robot. The system, called Mahoro, is capable of learning techniques from the best laboratory technicians, then replicating them perfectly. That should make stem cell culturing procedures much more reproducible and significantly reduce the cost of deploying new therapies.

Hiromitsu Nakauchi, of Stanford University and the University of Tokyo, described his groups efforts to overcome a decades-old challenge in stem cell research. Scientists have known for over 25 years that all of the blood cells in a human are renewed from a tiny population of multipotent, self-renewing hematopoietic stem cells. In an animal thats had all of its hematopoietic lineages eliminated by ionizing radiation, a single such cell can reconstitute the entire blood cell population. This protocol is the basis for several experimental models.

In theory, then, a single hematopoietic stem cell should also be able to multiply indefinitely in pure culture, allowing researchers to produce all types of blood cells on demand. In practice, cultured stem cells inevitably differentiate and die off after just a few generations in culture. Nakauchi and his colleagues have been trying to fix that problem. After years of hard work, we decided to take the reductionist approach and try to define the components that we use to culture [hematopoietic stem cells], said Nakauchi.

The team focused on the most undefined component of their culture media: bovine serum albumin (BSA). This substance, a crude extract from cow blood, has been considered an essential component of growth media since researchers first managed to culture mammalian cells. However, Nakauchis lab found tremendous variation between different lots of BSA, both in the types and quantities of various impurities in them and in their efficacy in keeping stem cells alive. Worse, factors that appeared to be helpful to the cells in some BSA lots were harmful when present in other lots. So this is not science; depending on the BSA lot you use, you get totally different results, said Nakauchi.

Next, the researchers switched to a recombinant serum albumin product made in genetically engineered yeast. That exhibited less variation between lots, and after optimizing their culture conditions they were able to grow and expand hematopoietic stem cells for nearly a month. Part of the protocol they developed was to change the medium every other day, which they found was required to remove inflammatory cytokines and chemokines being produced by the stem cells. That suggested the cells were still under stress, perhaps in response to some of the components of the recombinant serum albumin.

Polyvinyl alcohol can replace BSA in culture medium.

The ongoing problems with serum albumin products led Nakauchi to ask why albumin is even necessary in tissue culture. Scientists have known for decades that cells dont grow well without it, but why not? While trying to figure out what the albumin was doing for the cells, Nakauchis lab tested it against the most inert polymer they could find: polyvinyl alcohol (PVA). Best known as the primary ingredient for making school glue, PVA is also used extensively in the food and pharmaceutical industries. To their surprise, hematopoietic stem cells grew better in PVA-spiked medium than in medium with BSA. The PVA-grown cells showed decreased senescence, lower levels of inflammatory cytokines, and better growth rates.

In long-term culture, Nakauchi and his colleagues were able to achieve more than 900-fold expansion of functional mouse hematopoietic stem cells. Transplanting these cells into irradiated mice confirmed that the cells were still fully capable of reconstituting all of the hematopoietic lineages. Further experiments determined that PVA-containing medium also works well for human hematopoietic stem cells.

Besides having immediate uses for basic research, the ability to grow such large numbers of hematopoietic stem cells could overcome a fundamental barrier to using these cells in the clinic. Current hematopoietic stem cell therapies require suppressing or destroying a patients existing immune system to allow the transplanted cells to become established, but this immunosuppression can lead to deadly infections. Transplanting a much larger population of stem cells can overcome the need for immunosuppression, but growing enough cells for this approach has been impractical. Using their new culture techniques, Nakauchis team can now produce enough hematopoietic stem cells to carry out successful transplants without immunosuppression in mice. They hope to take this approach into the clinic soon.

Brigid L.M. Hogan Duke University School of Medicine

Emmanuelle Passegu Columbia University Irving Medical Center

Hans Schler Max Planck Institute for Molecular Biomedicine

Austin Smith University of Cambridge

Moderator: Azim Surani University of Cambridge

Austin Smith, from the University of Cambridge, gave the final presentation, in which he discussed his studies on the progression of embryonic stem cells through development. In mammals, embryonic development begins with the formation of the blastocyst. In 1981, researchers isolated cells from murine blastocysts and demonstrated that each of them can grow into a complete embryo. Stem cells isolated after the embryo has implanted itself into the uterus, called epiblast stem cells, have lost that ability but gained the potential to differentiate into multiple cell lineages in culture. So we have two different types of pluripotent stem cells in the mouse, and theyre different in just about every way you could imagine, said Smith.

Work on other species, including human cells, suggests that this transition between two different types of stem cells is a common feature of mammalian development. The transition from the earlier to the later type of stem cell is called capacitation. To find the factors driving capacitation, Smith and his colleagues looked for differences in gene transcription patterns and chromatin organization during the process, in both human and murine cells. What they found was a global re-wiring of nearly every aspect of the cells physiology. Together these things lead to the acquisition of both germline and somatic lineage competence, and at the same time decommission that extra-embryonic lineage potential, Smith explained.

Having characterized the cells before and after capacitation, the researchers wanted to isolate cells from intermediate stages of the process to understand how it unfolds. To do that, they extracted cells from mouse embryos right after implantation, then grew them in culture conditions that minimized their exposure to signals that would direct them toward specific lineages. Detailed analyses of these cells, which Smith calls formative stem cells, shows that they have characteristics of both the naive embryonic stem cells and the later epiblast stem cells. Injecting these cells into mouse blastocysts yields chimeric mice carrying descendants of the injected cells in all their tissues. The formative stem cells can therefore function like true embryonic stem cells, albeit less efficiently.

The developmental sequence of pluripotent cells.

Post-implantation human embryos arent available for research, but Smiths team was able to culture naive stem cells and prompt them to develop into formative stem cells. These cells exhibit transcriptional profiles and other characteristics homologous to those seen in the murine formative stem cells.

Having found the intermediate cell type, Smith was now able to assemble a more detailed view of the steps in development. Returning to the mouse model, he compared the chromatin organization of naive embryonic, formative, and epiblast stem cells. The difference between the naive and formative cells chromatin was much more dramatic than between the formative and epiblast cells.

Based on the results, Smith proposes that naive embryonic stem cells begin as a blank slate, which then undergoes capacitation to become primed to respond to later differentiation signals. The capacitation process entails a dramatic change in the cells transcriptional and chromatin organization and occurs around the time of implantation. We think we now have in culture a cell that represents this intermediate stage and that has distinctive functional properties and distinctive molecular properties, said Smith. After capacitation, the formative stem cells undergo a more gradual shift to become primed stem cells, which are the epiblast stem cells in mice.

Smith concedes that the human data are less detailed, but all of the experiments his team was able to do produced results consistent with the mouse model. Other work has also found corroborating results in non-human primate embryos, implying that the same developmental mechanisms are conserved across mammals.

After the presentations, a panel consisting of members of the Innovators in Science Awards Scientific Advisory Council and Jury took the stage to address a series of questions from the audience.

The panel first took up the question of how researchers can better study human stem cells, given the ethical challenges of working with embryos. Brigid Hogan described organoid cultures, in which researchers stimulate human iPS cells to grow into minuscule organ-like structures. This is a way of looking at human development at a stage when its [otherwise] completely inaccessible, said Hogan. Other speakers concurred, adding that implanting human organoids into mice provides an especially useful model.

Another audience member asked about the potential for human stem cell therapy in the brain. Hogan pointed to the use of fetal cells for treating Parkinsons disease as an example, but panelist Hans Schler suggested that that could be a unique case. Patients with Parkinsons disease suffer from deficiency in dopamine-secreting neurons, so implanting cells that secrete dopamine in the correct brain region may provide some relief.

Panelists also addressed the use of stem cells in regenerative medicine, where researchers are targeting the nexus of aging, nutrition, and brain health. Emmanuelle Passegu explained that the bodys progressive failure to regenerate itself from its own stem cells is a hallmark of aging. I think we are getting to an era where transplantation or engraftment [of cells] will not be the answer, it will really be trying to reawaken the normal properties of the [patients own] stem cells, said Passegu.

As the meeting concluded, speakers and attendees seemed to agree that the field of stem cell research, like the cells themselves, is now poised to develop in a wide range of promising directions.

View original post here:
The New Transformers: Innovators in Regenerative Medicine - NYAS - The New York Academy of Sciences

Jansen Jones wasnt using her hands or legs.

She lacked muscle tone and was too weak to bear weight using her extremities.

The baby could lift and move her head, but she didnt seem as strong as a 5-month-old should be, her mother believed.

"She is my third child," Suzanne Jones said, which means she's witnessed developmental milestones twice previously.

Doctors at Childrens Healthcare of Atlanta diagnosed Jansen with a nonspecific, global developmental delay.

We were just told, She's behind. No big deal. Do some physical therapy, Jones said.

But a lot of babies seem really strong, and it was clear to Jones that Jansen was not.She would curl up in a sort of ball, and sat looking sweet and happy, but did not engage with her environment.

A neurologist said a muscle biopsy might explain the deficiency, but there are false positives with muscle biopsies.

"That is invasive and leaves a scar and scared us," Jones said. "You know, you're basically cutting on her arm or leg."

When Jansen didn't babble as expected, they started speech therapy. Then, they added occupational therapy.

"We just did hours and hours of therapies nonstop for years," Jones said.

A neuro-psychological exam led doctors to say Jansen was intellectually disabled.

This happened about the same time as rare, fleeting seizures caused Jansen to space out for a second or two.

An electroencephalogram (EEG) test confirmed abnormal electrical activity in her brain.

"Well, they just said she has epilepsy," Jones said.

But Jones said the family continually witnessed symptoms that suggested that Jansen was struggling in different ways.

The idea of genetic testing came up by the time Jansen was 3 years old.

"In my opinion, if it's genetics, that's the underlying cause of everything and so that should show us what is going on," Jones said.

Jones doctors described the 46 chromosomes in the body as chapters in a book. Whole exome sequencing was like scanning the book to see whether any chapters were missing or duplicated.

For example,the characteristic features and developmental problems of a person with Down Syndrome is caused by an extra chromosome 21.

Think of that as Chapter 21.

But after having Jansen's whole exome sequenced, they still had no solid answers.

"And so we got results back when she was 3 and it did not show us what was going on," Jones said.

All the Joneses could do was treat Jansen's symptoms, which included behavior problems.

Despite managing Jansen through applied behavior therapy and medication, Jansen acted out and shecouldn't control it. Nightmares made her want to sleep in bed with her parents.

"It's not clear to me why the whole exome sequencing didn't catch it," Jones said. But it's not an infallible test.

An exome is a collection of 180,000 exons responsible for protein coding, but the human exome only comprises about 1% of the human genome.

Now, whole genome sequencing is available.

"And that is what ended up catching it," Jones said.

Jansen was diagnosed just before her 11th birthday with a disorder caused by a single gene mutation: SYNGAP1.

"This mutation was discovered only a year before Jansen was born."

Jansen's frustration stemmed from an inability to reason and communicate.

She turned 13 in October 2023.

"It's not easy," Jones said. "They have a SYNGAP snap. Sometimes their brain just [goes] haywire. And you can't you can't reason with somebody who can't reason. So behaviors can be really difficult."

"Compared to other single-gene mutations that cause epilepsy, SYNGAP1 children have a lot of problems with behavior," Jones said. "And luckily with that being a spectrum, my child has those issues, but it's not constant; it's not as prevalent."

If you have a rare disease, there is an 80% chance that its genetic. That doesnt mean the cause has been identified yet.

Karen Grinzaid with Emory University School of Medicine said she believes everyone planning a family should conduct genetic testing.

"The reason is there are genetic diseases that can happen that haven't shown up in your family yet," she said.

We all carry a number of recessive genes, but we don't know what those genes are unless either we have an affected child, or we do genetic testing.

But a whole genome test like Jansens might make would-be parents more nervous than is necessary.

"When you do broader testing like that, it may turn up problems where it's not clear what the implications are," Grinzaid said. "So, I just can't overemphasize the importance of genetic counseling to help people through this journey."

Suzanne Jones said even though her daughters diagnosis hasnt changed her daughters developmental issues, the genomic sequencing was worth it.

"It's an answer," she said. "We can finally say we understand what all these different symptoms are caused by."

And that, Jones said, makes it a lot less scary to be a parent.

See the original post:
80% of rare diseases are genetic. That's why whole genome sequencing can help with diagnoses - GPB News

Mice

C57BL/6J (CD45.2) and C57BL6.SJL (CD45.1) mice were purchased from The Jackson Laboratory and housed under specific pathogen-free conditions. Male and female mice from 8 to 12 weeks were used in experiments and provided with a suitable environment and sufficient water and food. After a week of acclimatization, each mouse was randomly divided into groups, given 100L pure water, 0.01mg/100L, or 0.1mg/100L MPs by oral gavage every two days for five weeks in a gavage experiment (n=5 for each group). For the intravenous injection experiment, MPs were administered into mouse blood via the tail vein at a rate of 0.1g/100L per week for a duration of 4 weeks (n=5 for each group). All animal experiments were first approved by the Laboratory Animal Welfare and Ethics Committee of Zhejiang University (AP CODE: ZJU20220108).

Indocyanine green polystyrene (ICG-PS), polystyrene (PS) and polymethyl methacrylate (PMMA) particles were obtained from Suzhou Mylife Advanced Material Technology Company (China). Polyethylene (PE) particles were purchased from Cospheric (USA). Scanning electron microscopy (SEM, Nova Nano 450, FEI) was used to characterize the primary sizes and shapes of different MPs20. MPs were dispersed in ultrapure water with sonication before dynamic light scattering analysis (Zetasizer, Malvern, UK) to determine the hydrodynamic sizes and zeta potentials49.

Mice were sacrificed and organs were removed within six hours of ICG-PS gavage, including the heart, lung, kidney, spleen, liver, gastrointestinal tissues and bone marrow. Feces were collected 1h before the mice were sacrificed. Both organs and feces were monitored by ex vivo bioluminescence imaging with a small-animal imaging system50 (IVIS Spectrum, PerkinElmer).

For flow cytometry analysis and isolation of hematopoietic stem and progenitor cells, cells were stained with relevant antibodies51 in PBS with 2% fetal bovine serum for 3045min on ice. Antibody clones that were used: Sca-1-PE-Cy7, c-Kit-APC, CD150-PE, CD48-BV421, CD45.1-FITC, CD45.2 PE-Cy5, Gr-1-PE-Cy5, Mac1-PE-Cy5, IgM-PE-Cy5, CD3-PE-Cy5, CD4- PE-Cy5, CD8-PE-Cy5, CD45R-PE-Cy5 and Ter-119-PE-Cy5. Detailed antibody information is summarized in Supplementary Table S6. HSPCs were stained with a lineage antibody cocktail (Gr-1, Mac1, CD3, CD4, CD8, CD45R, TER119 and B220), Sca-1, c-Kit, CD150 and CD48. Cell types were defined as followed: LSK compartment (LinSca-1+c-Kit+), LT-HSC (LSK CD150+CD48), ST-HSC (LSK CD150CD48), MPP2 (LSK CD150+CD48+) and MPP3/4 (LSK CD150CD48+). B cells (CD45.2+Mac1Gr-1+B220+), T cells (CD45.2+Mac1Gr-1+CD3+) and myeloid cells (CD45.2+Mac1+Gr-1). Samples were analyzed on a flow cytometer (CytoFLEX LX, Beckman). For sorting HSCs, lineage antibody cocktail-conjugated paramagnetic microbeads and MACS separation columns (Miltenyi Biotec) were used to enrich Lin cells before sorting. Stained cells were re-suspended in PBS with 2% FBS and sorted directly using the Beckman moflo Astrios EQ (Beckman). Flow cytometry data were analyzed by FlowJo (BD) software.

Apoptosis of cells was detected by Annexin V staining (Yeason, China). After being extracted from the bone marrow of mice, 5106 cells were labeled with different surface markers for 30 to 45min at 4C and then twice rinsed with PBS. Subsequently, the cells were reconstituted in binding buffer and supplemented with Annexin V. After 30min of incubation, flow cytometry was detected in the FITC channel. Cell cycle analysis was performed with the fluorescein Ki-67 set (BD Pharmingen, USA), following the directions provided by the manufacturer. Briefly, a total of 5106 bone marrow cells were labeled with corresponding antibodies, as previously stated. Afterward, the cells were pre-treated with a fixation/permeabilization concentrate (Invitrogen, USA) at 4C overnight and subsequently rinsed with the binding buffer. The cells were stained with Ki-67 antibody for 1h in the dark and then with DAPI (Invitrogen) for another 5min at room temperature. Flow cytometry data were collected by a flow cytometer (CytoFLEX LX, Beckman, USA).

HSCs were sorted by flow cytometry according to the experimental group (ctrl and PSH mice, Rikenellaceae treatment or hypoxanthine treatment). 150 HSCs were seeded in triplicate on methylcellulose media52 (M3434, Stemcell Technologies, Inc.). After 8 days, the number of colonies was counted by microscopy. In addition, 5000 BM cells were seeded and analyzed the same way as HSCs. The cell culture media was diluted in PBS and subjected to centrifugation at 400g for 5min to determine the total cell number.

Recipient mice (CD45.1) were administered drinking water with Baytril (250mg/L) for 7 days pre-transplant and 10 days post-transplant. The day before transplantation, recipients received a lethal dose of radiation (4.5Gy at a time, divided into two times with an interval of 4h). In primary transplantation, 2105 bone marrow cells from the ctrl or PS group (CD45.2) mice and 2105 recipient-type (CD45.1) bone marrow cells were transplanted into recipient mice (CD45.1) mice. Cells were injected into recipients via tail vein injection. Donor chimerism was tracked using peripheral blood cells every 4 weeks for at least 16 weeks after transplantation. For secondary transplantation, donor BM cells were collected from primary transplant recipients sacrificed at 16 weeks after transplantation and transplanted at a dosage of 2106 cells into irradiated secondary recipient mice (9Gy). Analysis of donor chimerism and the cycle of transplantation in secondary transplantation were the same as in primary transplantation.

For limiting dilution assays52, 1104, 5104 and 2105 donor-derived bone marrow cells were collected from ctrl or PS mice (CD45.2) and transplanted into irradiated (9Gy) CD45.1 recipient mice with 2105 recipient-type (CD45.1) bone-marrow cells. Limiting dilution analysis was performed using ELDA software53. 16 weeks after transplantation, recipient mice with more than 1% peripheral-blood multilineage chimerism were defined as positive engraftment. On the other hand, recipient mice undergoing transplantation that had died before 16 weeks post transplantation were likewise evaluated as having failed engraftment54.

For histological analysis, small intestines were collected and fixed in 4% paraformaldehyde and embedded in paraffin, sectioned (5m thickness), and stained with H&E at ZJU Animal Histopathology Core Facility (China). We used Chius scores33,34 to evaluate the damage for each sample. The grade was as follows: 0, normal mucosa; 1, development of subepithelial Gruenhagens space at the tip of villus; 2, extension of the Gruenhagens area with moderate epithelial lifting; 3, large epithelial bulge with a few denuded villi; 4, denuded villi with lamina propria and exposed capillaries; and 5, disintegration of the lamina propria, ulceration, and hemorrhage. For TEM analysis, slices of the small intestine were fixed with 2.5% glutaraldehyde for ultra-microstructure observation of intestinal epithelial cells. The samples were postfixed for one hour at 4C with 1% osmium tetroxide and 30min with 2% uranyl acetate, followed by dehydration with a graded series of alcohol solutions (50%, 70%, 90% and 100% for 15min each) and acetone (100% twice for 20min). Subsequently, they were embedded with epon (Sigma-Aldrich, MO, US) and polymerized. Ultrathin sections (6080nm) were made, and examined using TEM (Tecnai G2 Spirit 120kV, Thermo FEI).

In the short-term and long-term mouse models for MP ingestion, mice were fasted for 4h before oral gavage of FITC-dextran (4kD, Sigma). The fluorescence intensity of FITC-dextran (50mg/100g body weight) was measured in the peripheral blood after 2h of gavage. Fluorescence was measured using a microplate reader (Molecular Devices, SpectraMax iD5) with excitation at 490nm and emission at 520 nm29.

Fecal samples (about 3050mg per sample) were collected from the ctrl, PSL and PSH mice, quickly frozen in liquid nitrogen, and stored at 80C. DNA samples for the microbial community were extracted using E.Z.N.A. Stool DNA Kit (Omega, USA), according to the manufacturers instructions. In brief, polymerase chain reaction (PCR) amplification of prokaryotic 16S rDNA gene V3V4 region was performed using the forward primer 341F (5-CCTACGGGNGGCWGCAG-3) and the reverse primer 805R (5-GACTACHVGGGTATCTAATCC-3)55. After 35 cycles of PCR, sequencing adapters and barcodes were included to facilitate amplification. The PCR products were detected by 1.5% agarose gel electrophoresis and were further purified using AMPure XT beads (Beckman Coulter Genomics, Danvers, MA, USA), while the target fragments were recovered using the AxyPrep PCR Cleanup Kit (Axygen, USA). In addition, the amplicon library was quantified with the Library Quantification Kit for Illumina (Kapa Biosciences, Woburn, MA, USA), and sequenced on the Illumina NovaSeq PE250 platform. In bioinformatics pipeline29,56, the assignment of paired-end reads to samples was determined by their unique barcode, and subsequently shortened by cutting off the barcode and primer sequence. The paired-end reads were combined by FLASH (v1.2.8). Quality filtering on the raw reads was carried out under precise parameters to obtain high-quality clean tags according to fqtrim (v0.94). The chimeric sequences were filtered by Vsearch software (v2.3.4). After the dereplication process using DADA2, we acquired a feature table and feature sequence. The bacterial sequence fragments obtained were grouped into Operational Taxonomic Units (OTUs) and compared to the Greengenes microbial gene database using QIIME2. Alpha diversity and beta diversity were generated by QIIME2, and pictures were drawn by R (v3.2.0). The species annotation sequence alignment was performed by Blast, with the SILVA and NT-16S databases as the alignment references. Additional sequencing results are provided in Supplementary Table S1. The experiment was supported by Lc-Bio Technologies.

The methods for the analysis of feces from HSCT donors were slightly different from those used for mice. All samples were stored in the GUHE Flora Storage buffer (GUHE Laboratories, China). The bacterial genomic DNA was extracted with the GHFDE100 DNA isolation kit (GUHE Laboratories, China) and quantified using a NanoDrop ND-1000 spectrophotometer (Thermo Fisher Scientific, USA). The V4 region of the bacterial 16S rDNA genes was amplified by PCR, with the forward primer 515F (5-GTGCCAGCMGCCGCGGTAA-3) and the reverse primer 806R (5-GGACTACHVGGGTWTCTAAT-3). PCR amplicons were purified with Agencourt AMPure XP Beads (Beckman Coulter, IN) and quantified by the PicoGreen dsDNA Assay Kit (Invitrogen, USA). Following the previously reported steps57, the paired-end 2150bp sequencing was performed on the Illumina NovaSeq6000 platform. The details of bacterial OTUs are summarized in Supplementary Table S5. Sequence data analyses were performed using QIIME2 and R packages (v3.2.0).

For metabolite evaluation, samples from mice feces were prepared and detected as previously described55,58,59. In a nutshell, metabolites were extracted from feces through precooled 50% methanol buffer and stored at 80C before the LCMS analysis. All chromatographic separations were conducted using an ultra-performance liquid chromatography (UPLC) system (SCIEX, UK). A reversed phase separation was performed using an ACQUITY UPLC T3 column (100mm * 2.1mm, 1.8m, Waters, UK). The temperature of the column oven was maintained at 35C and the flow rate was 0.4mL/min. Both positive (the ionspray voltage floating set at 5000V) and negative ion modes (4500V) were analyzed using a TripleTOF 5600 Plus high-resolution tandem mass spectrometer (SCIEX, UK). The mass spectrometry data were obtained in Interactive Disassembler Professional (IDA) mode, with a time-of-flight (TOF) mass range of 60 to 1200Da. The survey scans were acquired in 150 milliseconds and product ion scans with a charge state of 1+ and 100 counts per second (counts/s) were recorded up to 12. Cycle duration was 0.56s. Stringent quality assurance (QA) and quality control (QC) procedures were applied, as the mass accuracy was calibrated every 20 samples and a QC sample was obtained every 10 samples. LCMS raw data files underwent processing in XCMS (Scripps, La Jolla, CA) to perform peak picking, peak alignment, gap filling, and sample normalization. Online KEGG was adopted to annotate metabolites through the matching between the precise molecular mass data (m/z) of samples and those from the database. PCA and volcano plot were utilized to identify ion characteristics that exhibit significant differences between the groups. The details of metabolomes can be found in Supplementary Table S2. The experiment was supported by Lc-Bio Technologies.

Before FMT, SPF mice received a 200L antibiotic treatment (1g/L ampicillin, 0.5g/L neomycin, 0.5g/L vancomycin and 1g/L metronidazole) for three consecutive days by oral gavage. Fresh feces were collected from ctrl or PS mice and resuspended in reduced PBS (0.5g/L cysteine and 0.2g/L Na2S in PBS) at a ratio of about 120mg feces/mL reduced PBS. Feces were then centrifuged at 500g for 1min to remove insolubilize particles25. Recipients (C57BL/6J mice) were administered 100mL of the supernatant from different groups by oral gavage twice every week for 4 weeks. 2 days after the last FMT, recipients were euthanized to analyze the changes in the hematopoietic system.

The Rikenellaceae strain (ATCC BAA-1961), purchased from ATCC, was cultured in an anaerobic chamber using BD Difco Dehydrated Culture Media: Reinforced Clostridial Medium at a temperature of 37C with a gas mixture of 80% N2 and 20% CO2. The final concentration of Rikenellaceae was 2108 viable c.f.u. per 100L and hypoxanthine (200mg/kg, Sigma, Germany) was dissolved in double distilled water29. Mice first received antibiotic treatment (same as FMT) and were then treated by oral gavage with 100L of either Rikenellaceae or hypoxanthine suspension three times a week for 4 weeks. Reinforced Clostridial Medium or double distilled water was used as a vehicle control, respectively. 2 days after the last administration, recipients were euthanized to analyze the changes in the hematopoietic system. To examine the impact of hypoxanthine on HSCs, we exposed bone marrow cells to direct co-culture with hypoxanthine at a concentration of 100pg/mL for a period of 3 days.

Mouse bone marrow cells were harvested by flushing the mices tibia and femur in phosphate buffered saline (PBS) with 2% fetal bovine serum (GIBCO). Harvested cells were grown into 96-well u-bottom plates containing freshly made HSC culture medium (StemSpanTM SFEM, Stemcell Tec.) with SCF (50ng/mL; PeproTech) and TPO (50ng/mL; PeproTech), at 37C with 5% CO2. For HSC culture, the medium was changed every 3 days by manually removing half of the conditioned medium and replacing it with fresh medium60. To assess the effects of WNT10A, IL-17, TNF and NF-kappa B on hematopoiesis, we cultured HSCs in a basic medium and supplemented them with related proteins (10ng/mL; Cosmo Bio, USA) or PBS as a control for two days, followed by flow cytometry analysis. Different concentrations of PS were added to the medium and tested using CCK-8 and FACS to detect the effect of MPs on cultured HSCs.

1104 HSCs were obtained in triplicate from mouse bone marrow cells from the ctrl or PSH group by flow cytometry sorting and RNA was extracted with RNAiso Plus (Takara, Japan) according to the manufacturers protocol. The concentration and integrity of RNA were examined by Qubit 2.0 and Agilent 2100 (Novogene, China), respectively. Oligo (dT)-coated magnetic beads (Novogene, China) were used to enrich eukaryotic mRNA. After cDNA synthesis and PCR amplification, the PCR product was purified using AMPure XP beads (Novogene, China) to obtain the final library. The Illumina high-throughput sequencing platform NovaSeq 6000 was used for sequencing. Analysis of gene expression was calculated by R or the DESeq2 package61. Detailed information regarding RNA-seq is listed in Supplementary Table S3.

For RNA expression analysis, total RNA from bone marrow cells was extracted using Trizol (Invitrogen, US) and resuspended in nuclease-free water. Reverse transcription was performed using the QuantiTect Reverse Transcription kit (Qiagen NV). qPCR was conducted using cDNA, primers and SYBR-green (Takara, Japan) in 20L using the ABI 7500 Q-PCR system62. Results were calculated using the RQ value (RQ=2Ct). Mouse Actin was chosen as the normalization control. Gene-specific primer sequences are shown in Supplementary Table S7.

Bone marrow and Rikenellaceae supernatant in different groups were obtained by centrifugation. Fecal supernatant was obtained from human samples. Hypoxanthine (LANSO, China) and WNT10A (EIAab, China) were measured by ELISA with respective kits according to the manufacturers protocols.

Human feces and peripheral blood samples were obtained from 14 subjects who provided grafts for HSCT patients. They were divided into graft success group and graft failure (GS)/poor graft function (GF/PGF) group, with 7 participants in each group. Research involving humans was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (IIT20230067B). All participants read and signed the informed consent. Detailed information on patients was listed in Supplementary Table S4.

The Agilent 8700 Laser Direct Infrared Imaging system was utilized for fast and automated analysis of MPs in feces received from donors. An excessive nitric acid concentration (68%) was added to the sample and heated to dissolve the protein. Large particles were first intercepted with a large aperture filter and then filtered by vacuum extraction. After rinsing with ultra-pure water and ethanol several times, the materials, including MPs, were dispersed in the ethanol solution. The LDIR test was carried out when the ethanol was completely volatilized63. The sample of MPs was positioned on the standard sample stage. The stage was then put into the sample stage, and the Agilent Clarity was initiated to advance the sample stage into the sample chamber. The software rapidly scanned the chosen test area using a constant wave number of 1800cm1, and accurately detected and pinpointed the particles within the selected area. The unoccupied area devoid of particles was automatically designated as the background. The background spectrum was gathered and readjusted, followed by the visualization of detected particles and the collection of the whole infrared spectrum. After obtaining the particle spectrum, the spectrum library was utilized to carry out qualitative analysis automatically, including the inclusion picture, size, and area of each particle. The test was supported by Shanghai WEIPU Testing Technology Group.

MPs in peripheral blood from donors were tested by Py-GC/MS. Nitric acid was added to samples for digestion at 110C for 12h, and then used deionized water to make the solution weakly acidic. After concentration, the solution was dribbled into the sampling crucible of Py-GCMS and tested when the solvent in the crucible was completely volatilized17. Various standards of MPs were prepared and analyzed using Py-GCMS in order to construct the quantitative curve. PY-3030D Frontier was employed for lysis, with a lysis temperature set at 550 C. The chromatographic column dimensions were 30m in length, 0.25mm inner diameter, and 0.25m film thickness. The sample was subjected to a heat preservation period of 2min at 40C, followed by a gradual increase in temperature at a rate of around 20C per minute until it reached 320C. The sample was maintained at this temperature for 14min and the entire process takes a total of 30min. The carrier gas utilized was helium, with the ion source temperature of 230C. The split ratio employed was 5:1, and the m/z scan range spanned from 40 to 60064. The experiment was supported by Shanghai WEIPU Testing Technology Group.

Each animal experiment was tested using at least 56 replicates and each in vitro experiment was at least three replicates. Specific replication details are provided in relevant figure captions. Statistical significance was ascertained through unpaired two-tailed t-tests by GraphPad Prism when the P value was less than 0.05. Error bars in all figures indicate the standard deviation (SD).

Link:
Microplastics dampen the self-renewal of hematopoietic stem cells by disrupting the gut microbiota-hypoxanthine-Wnt ... - Nature.com

Co-author Steven Gray, Ph.D., is Associate Professor of Pediatrics, Molecular Biology, Neurology, and in the Eugene McDermott Center for Human Growth and Development at UTSouthwestern.

DALLAS March27, 2024 A gene therapy developed by researchers at UTSouthwestern Medical Center for a rare disease called giant axonal neuropathy (GAN) was well tolerated in pediatric patients and showed clear benefits, a new study reports. Findings from the phase one clinical trial, published in the New England Journal of Medicine, could offer hope for patients with this rare condition and a host of other neurological diseases.

This trial was the first of its kind, for any disease, using an approach to broadly deliver a therapeutic gene to the brain and spinal cord by an intrathecal injection, said co-author Steven Gray, Ph.D., Associate Professor of Pediatrics, Molecular Biology, Neurology, and in the Eugene McDermott Center for Human Growth and Development at UTSouthwestern. Even with the relatively few patients in the study, there were clear and statistically significant benefits demonstrated in patients that persisted for years.

Dr. Gray developed this gene therapy with co-author Rachel Bailey, Ph.D., Assistant Professor in the Center for Alzheimers and Neurodegenerative Diseases and of Pediatrics at UTSW.Dr. Gray is an Investigator in thePeter ODonnell Jr. Brain Institute.

GAN is extraordinarily rare, affecting only about 75 known families worldwide. The disease is caused by mutations in a gene that codes for a protein called gigaxonin. Without normal gigaxonin, axons the long extensions of nerve cells swell and eventually degenerate, leading to cell death. The disease is progressive, typically starting within the first few years of a childs life with symptoms including clumsiness and muscle weakness. Patients later lose the ability to walk and feel sensations in their arms and legs, and many gradually lose hearing and sight and die by young adulthood.

In the clinical trial conducted at the National Institutes of Health (NIH), Drs. Gray and Bailey worked with colleagues from the National Institute of Neurological Disorders and Stroke (NINDS) to administer the therapy to 14 GAN patients from 6 to 14 years old. Using a technique they developed to package the gene for gigaxonin into a virus called adeno-associated virus 9 (AAV-9), the researchers injected it into the intrathecal space between the spinal cord and the thin, strong membrane that protects it. Tested for the first time for any disease, this approach enabled the virus to infect nerve cells in the spinal cord and brain to produce gigaxonin in nerve cells, allowing them to heal the cells axons, which grow throughout the body.

Amanda Grube, 14, one of the trial's participants, has seen improvement in her diaphragm and other muscles associated with breathing, her mother says. However, many of Amanda's other functions, including her mobility, did not benefit. (Photo credit: McKee family)

After one injection, the researchers followed the patients over a median of nearly six years to determine whether the treatment was safe and effective. Only one serious adverse event was linked to the treatment fever and vomiting that resolved in two days suggesting it was safe. Over time, some patients showed significant recovery on an assessment of motor function. Other measurements revealed that several of the patients improved in how their nerves transmitted electrical signals.

One of the trials participants, 14-year-old Amanda Grube, has experienced improvement in her diaphragm and other muscles associated with breathing, according to her mother, Katherine McKee. However, many of Amandas other functions did not benefit including her mobility.

Thats why I hope theres more to come from the research that can help patients even more,Mrs. McKee said. Amanda has dreams and ambitions. She wants to work with animals, save the homeless, and design clothes for people with disabilities.

Dr. Gray said that in many ways, the study offers a road map to carry out similar types of clinical trials. The findings have broader implications because this study established a general gene therapy treatment approach that is already being applied to dozens more diseases, he said.

Although the phase one results are promising, Dr. Gray said he and other researchers will continue to fine-tune the treatment to improve results in future GAN clinical trials. He is also using this method for delivering gene therapies to treat other neurological diseases at UTSW, where he is Director of the Translational Gene Therapy Core, and at Childrens Health. Work in theGray Labhas already led to clinical trials for diseases including CLN1 Batten disease, CLN5 Batten disease, CLN7 Batten disease, GM2 gangliosidosis, spastic paraplegia type 50, and Rett syndrome.

The GAN study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), Division of Intramural Research, NIH; Hannahs Hope Fund; Taysha Gene Therapies; and Bamboo Therapeutics-Pfizer.

Drs. Bailey and Gray are entitled to royalties from Taysha Gene Therapies. Dr. Gray has also consulted for Taysha and serves as Chief Scientific Adviser.

About UTSouthwestern Medical Center

UTSouthwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

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Gene therapy offers hope for giant axonal neuropathy patients - UT Southwestern

According to latest study, the global advanced therapy medicinal products CDMO Market size was valued at USD 6.10 billion in 2023 and is projected to reach USD 34.53 billion by 2033, growing at a CAGR of 18.93% from 2024 to 2033.

Key Takeaways:

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owing to risingclinical trialsfor advanced therapy medicinal products and the increasing awareness among researchers about the benefits of advanced therapies, driving the advanced therapy medicinal products (ATMP) CDMO market growth. Tissue engineering has greatly benefited in recent years from technological development. The damaged tissues and organ function are replaced or restored using this technique. Similarly, gene and cell therapy are attracting a lot of patients for the treatment of rare diseases, whose incidence is rising globally.

With rising demand for robust disease treatment therapies, key players have focused their efforts to ramp up research and development for effective gene therapies that target the cause of disorder at a genomic level. According to ASGCT, the number of cell and gene therapies in the U.S. pipeline programs (phase I-III trials) increased from 483 in 2021 to 529 in 2022. Furthermore, the FDA delivers constant support for innovations in the gene therapy field via a number of policies with regard to product manufacturing. In January 2020, the agency released six final guidelines on the manufacturing and clinical development of safe & efficient gene therapy products.

Moreover, awareness about ATMP treatment options is being driven by initiatives aimed at informing the public about the benefits of these products, which, in turn, is leading to increased adoption of advanced therapies and fueling market growth for CDMOs. For instance, Alliance for Regenerative Medicine Foundation for Cell and Gene Medicine prioritizes activities for increasing public awareness through educational programs, underlining the clinical & societal benefits of regenerative medicine.

Increasing clinical trial activity along with new product launches generates growth opportunities for the market. As of 2022, there are 1451 ATMPs in preclinical stages and 535 are being studied in Phase 1 to 3 studies. Since August 2020, EMA has approved six of these additional ATMPs, and five more will be approved by 2023. In the UK, there were approximately 168 advanced therapy medicinal product trials underway in 2021, up from the 154 studies reported the year before, which is a 9% increase. 2021 saw a 32% increase in phase 1 trials, indicating a significant shift from experimental medicines to first-in-human studies.

On the other hand, key players are undertaking various strategic initiatives to introduce novel products, which is expected to propel market growth. For instance, in March 2021, CureVac N.V. signed a partnership agreement with Celonic Group, engaged in the manufacture of CVnCoV, CureVacs mRNA-based COVID-19 vaccine candidate. CureVac's COVID-19 vaccine candidate is manufactured at Celonic's commercial manufacturing unit for ATMPs and biologics in Heidelberg, Germany. Under the terms of the commercial supply agreement, the Celonic facility could produce over 100 million doses of CVnCoV.

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Advanced Therapy Medicinal Products CDMO Market Trends

Segments Insights:

Product Insights

The gene therapy segment held the largest share of over 49.11% in 2023. Increase in financial support and rise in number of clinical trials for gene therapies are driving demand for gene therapy segment. In 2020, in the first three quarters, gene therapies attracted financing of over USD 12 billion globally, with around 370 clinical trials underway. Additionally, in mid-2022, approximately 2,000 gene therapies were in development, targeting several therapeutic areas, such as neurological, cancer, cardiovascular, blood, and infectious diseases.

The cell therapy segment is expected to show lucrative growth over the forecast period. The field of cellular therapeutics is constantly advancing with inclusion of new cell types, which, in turn, provides ample opportunities for companies to enhance their market positions. Furthermore, the market is attracting new entrants due to high unmet demand for cell therapy manufacturing, the recent approval of advanced therapies, and proven effectiveness of these products.

Indication Insights

The oncology segment accounted for the largest revenue share in 2023. The segments dominance is attributed to disease burden, strategic initiatives undertaken by key players, and availability of advanced therapies used for treating various cancer indications. In January 2021, around 18,000 to 19,000 patients and 124,000 patients were estimated to be potential patients for treating cancer using cell & gene therapy products Kymriah (Novartis AG) and Yescarta (Gilead Sciences, Inc.), respectively. Furthermore, a publication on PubMed reports that as of the conclusion of the first quarter of 2023, there have been over 100 distinct gene, cell, and RNA therapies approved globally, along with an additional 3,700-plus in various stages of clinical and preclinical development.

The cardiology segment is estimated to register the fastest CAGR over the forecast period. This is attributed to the increasing prevalence of cardiovascular diseases and research collaboration for development of advanced therapies. For instance, in October 2023, Cleveland Clinic administered a novel gene therapy to the first patient globally as part of a clinical trial, aiming to deliver a functional gene to combat the primary cause of hypertrophic cardiomyopathy (HCM). Similarly, in February 2021, Trizell GmbH entered into partnership with Catalent, Inc. for development of phase 1 cell therapy to treat micro- and macroangiopathy. Trizell's medication is an Advanced Therapy Medicinal Product (ATMP) that employs regulatory macrophagesa platform technology developed in Germany.

Phase Insights

The phase I segment dominated the market in 2023 due to growing R&D activities and increasing number of human trials for advanced therapies. Phase 1 helps ensure the safety levels of a drug at different doses and dosage forms administered to a small number of patients. This phase is mainly conducted to determine the highest dose a patient can take without any adverse effects. Around 70% of drugs in phase 1 move to the next phase.

The phase II segment has been anticipated to show lucrative growth over the forecast period. Phase II clinical studies comprise the largest number of developing ATMPs, due to the high clearance rate of phase I clinical studies. According to data published by Alliance for Regenerative Medicine, as of June 2022, more than 2,093 clinical trials are ongoing globally, out of which 1,117 are under phase II clinical trials accounting for 53%. Thus, the increase in number of products in phase II is driving the segment.

Regional Insights

North America dominated the overall market share of 49.11% in 2023. This can be attributed to increasing outsourcing activities and rising awareness about advanced therapy. North America has consistently been a leader in R&D for advanced treatments, and it is anticipated that it will keep this position during the forecast period. Recent approvals of products such as Kymriah and Yescarta have propelled investments in the regional market. Moreover, in March 2021, the U.S. FDA approved Abecma, the first approval of CAR-T cells to fight against cancer. Similarly, in December 2023, Casgevy and Lyfgenia, the initial cell-based gene therapies for sickle cell disease (SCD) in patients aged 12 and above, received approval from the U.S. Food and Drug Administration, marking a significant milestone.

The U.S. accounted for the largest share of the global market in the North America region in 2023. The U.S. maintains dominance in this sector due to the presence of a robust and highly advanced biopharmaceutical industry with a considerable focus on research and development. Additionally, the continuous presence of numerous pharmaceutical and biotechnology companies, along with academic and research institutions, generates a sustained demand for rigorous safety testing, further reinforcing the country's leadership in the field.

The Asia Pacific region is expected to grow at the fastest CAGR over the forecast period due to the increasing demand for novel ATMPs and rising R&D activities to develop novel therapies. Moreover, the market growth is driven by continuously expanding CDMO Cell Therapy in the country, a number of domestic players have collaborated with biotech companies from other countries involved in mesenchymal stem cell research and therapy development. In addition, in September 2022 Takara Bio, Inc. launched CDMO Cell Therapy for gene therapy products using siTCR technology for its genetically modified T-cell therapy products.

China accounted for the largest share of the global market in the Asia Pacific region in 2023 due to its strategic focus on advancing research and development capabilities, particularly in the pharmaceutical and biotechnology sectors. Additionally, with a rapidly growing biopharmaceutical industry and supportive government initiatives, China has become a key market for advanced therapy medicinal products (CDMO) market.

Recent Developments

Key Companies & Market Share Insights

Some of the key players operating in the market include AGC Biologics,WuXi Advanced Therapies and Celonic

Minaris Regenerative Medicine and BlueReg are some of the emerging market players in the global market.

Key Advanced Therapy Medicinal Products CDMO Companies:

Segments Covered in the Report

This report forecasts revenue growth at country levels and provides an analysis of the latest industry trends in each of the sub-segments from 2021 to 2033. For this study, Nova one advisor, Inc. has segmented the Advanced Therapy Medicinal Products CDMO market.

By Product

By Phase

By Indication

By Region

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