Top 3 grants in regenerative medicine: May 2023
This month’s top grants in regenerative medicine, sourced from Dimensions, include projects on: high-resolution lineage tracing of developmental hematopoiesis, ROS signaling in wound healing versus tissue repair and microglia engineering and replacement to treat brain disease.
High-resolution lineage tracing of developmental hematopoiesis
ROS signaling in wound healing vs tissue repair
Microglia engineering and replacement to treat brain disease
High-resolution lineage tracing of developmental hematopoiesis
This project aims to investigate the developmental origins of hematopoiesis as, at present, there is limited data analyzing the long-term fate of the earliest hematopoietic progenitor cells and a lack of understanding of where the cells that become lifelong progenitors originate. Novel strategies, including the use of in situ mammalian barcoding, will be employed to perform lineage tracing at the single-cell level. Uncovering the basic mechanisms of blood development will provide avenues for future investigation and could uncover potential opportunities for therapeutic manipulation.
Funding amount: US$777,500
Funding period: 5 May 2023 – 28 February 2027
Funder: National Heart Lung and Blood Institute (NHLBI)
Research organization: Boston Children's Hospital (MA, USA)
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ROS signaling in wound healing vs tissue repair
It has been established that reactive oxygen species (ROS) are important for wound healing, however, current data indicate that ROS have both positive and negative impacts. Additionally, it is not entirely clear whether wound healing and regeneration are independent processes. Preliminary data suggests that different ROS signaling pathways exist for wound healing and regeneration and, based on this, this research project aims to pinpoint the differences in these ROS signaling pathways and investigate how they can be manipulated to regulate wound healing and tissue repair. In the long term it is hoped that advancing the understanding of how ROS is implicated in these processes will enable the identification of new targets for treatment for impaired wound healing and fibrosis and improve current therapy options.
Funding amount: US$444,329
Funding period: 1 May 2023 – 30 April 2026
Funder: National Institute of General Medical Sciences (NIGMS)
Research organization: Western Michigan University (MI, USA)
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Microglia engineering and replacement to treat brain disease
The goal of this research is to establish an approach for the specific and near-complete replacement of embryonic microglia with adoptively transferred progenitors, which could transform how many brain diseases are treated. The research will then combine iPSC differentiation with genetic barcoding, single-cell analysis and in vivo screening to identify progenitors that can successfully traffic to and engraft in the brain. Additionally, with the intention of utilizing transplanted microglia as a treatment for neurodegenerative diseases, the research team will investigate methods for transforming these cells into local protein production factories.
Funding amount: US$2,222,071
Funding period: 1 May 2023 – 30 April 2028
Funder: European Commission (EC)
Research organization: Vrije Universiteit Brussel (Brussels, Belgium)
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on 2023-06-05
Cell therapy weekly: Positive results for CRISPR-based microbial gene therapy
This week: SNIPR Biome (Copenhagen, Denmark) reported positive interim results for its CRISPR-based microbial gene therapy targeting E. coli; the US FDA accepted Iovance Biotherapeutics’ (CA, USA) Biologics License Application for their advanced melanoma tumor-infiltrating lymphocyte therapy; and AVROBIO (MA, USA) has sold its cystinosis gene therapy program to Novartis (Basel, Switzerland) for US$87.5 million.
The news highlights:
SNIPR Biome reports positive clinical interim results for CRISPR-based microbial gene therapy
US FDA accepts Iovance’s Biologics License Application for advanced melanoma cell therapy
AVROBIO sells cystinosis gene therapy program to Novartis for US$87.5 million
SNIPR Biome reports positive clinical interim results for CRISPR-based microbial gene therapy
SNIPR Biome, the company pioneering CRISPR-based microbial gene therapy, has announced positive interim results from its Phase I clinical trial of SNIPR001. SNIPR001 is a novel CRISPR-Cas therapeutic that targets antibiotic-resistant E. coli in the gastrointestinal tract, which can cause life-threatening infections in vulnerable patients. The study of 36 healthy individuals found that the drug was well tolerated and successfully lowered E. coli levels in the gut.
"We are thrilled with these positive interim results from our Phase 1 clinical trial of SNIPR001, which provide clinical validation for this innovative treatment. This is a significant milestone in our mission to develop groundbreaking solutions in the fight against antimicrobial resistance, and we look forward to advancing SNIPR001 through further clinical studies to learn more and ultimately, we hope, to improve patient outcomes," commented Christian Grøndahl, CEO and co-founder of SNIPR Biome.
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US FDA accepts Iovance’s Biologics License Application for advanced melanoma cell therapy
Iovance Biotherapeutics , a company that develops tumor-infiltrating lymphocyte (TIL) therapies, has announced that the US FDA has accepted their Biologics License Application for lifileucel, a TIL therapy for patients with advanced melanoma who progressed on or after prior anti-PD-1/L1 therapy and targeted therapy. The FDA granted lifileucel Priority Review, a program that expedites the review process for drugs that would significantly improve the safety or effectiveness of treatments for a serious condition. They have assigned 25 November 2023 as the target action date for a decision under the Prescription Drug User Fee Act.
Frederick Vogt, Interim President and CEO of Iovance, commented, “The BLA acceptance is a significant milestone in our mission to deliver lifileucel as the first individualized, one-time cell therapy for a solid tumor. The FDA’s commitment to a six-month Priority Review validates the unmet need and urgency for new treatment options for patients with advanced melanoma who have progressed on or after standard of care therapies.”
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AVROBIO sells cystinosis gene therapy program to Novartis for US$87.5 million
Leading clinical-stage gene therapy company AVROBIO, whose main focus is lysosomal disorders, has announced an agreement to sell its investigational hematopoietic stem cell gene therapy program for the treatment of cystinosis to Novartis for US$87.5 million in cash.
“This transaction strengthens AVROBIO’s balance sheet, focuses our pipeline strategy and is a strong endorsement of our HSC gene therapy approach and plato® gene therapy platform,” commented Erik Ostrowski, AVROBIO’s interim CEO and current CFO.
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on 2023-06-01
The applications of exosomes: ask the experts
In this ‘Ask the experts’ feature, we have brought together a panel of experts from across the industry to share their current perspectives on exosomes. For example, what are the main benefits of using exosomes and how do they compare to other therapeutics? What should be considered when selecting media for the isolation of exosomes and do these considerations differ depending on the cell source? And how can exosomes be isolated on a large scale while maintaining their quality? Discover more on the topic with our panel of thought leaders, featuring Lisa Hamelmann (PromoCell; Heidelberg, Germany), Faezeh Shekari (Royan Institute; Tehran, Iran) and Steven M. Jay (University of Maryland; MD, USA).
Meet the Experts
At what level are you working with exosomes?
What are the main benefits of using exosomes and how do they compare to other therapeutics?
What are the limitations of manufacturing and using exosomes?
What should be considered when selecting media for the isolation of exosomes and do these considerations differ depending on the cell source? (for example tumor-derived exosomes versus MSC-derived exosomes)
How can exosomes be isolated on a large scale while maintaining their quality?
How do you see the application of exosomes evolving in the next ten years?
Meet the Experts
Lisa Hamelmann
Product Manager
PromoCell
Lisa Hamelmann is a Product Manager at PromoCell (Heidelberg, Germany), a provider of primary, stem, blood and immune cells, as well as optimized cell culture media systems. Before she joined PromoCell in 2018, Dr Hamelmann worked on her PhD at the University Medicine of the Johannes Gutenberg-University (Mainz, Germany) where she investigated new therapeutic options for the treatment of autoimmune diseases. At PromoCell, Lisa started as a Scientific Support Specialist, working closely with clients from pharmaceutical and biotechnology industries. In 2020 she became Product Manager for cells and media, responsible for the stem cell portfolio and the introduction of custom-tailored solutions, such as the cancer cell media systems. As Product Manager she works closely with scientists to help them maximize their work with exosomes for different applications, including exosomes as cancer biomarkers or in the development of novel exosome-based therapeutics.
Faezeh Shekari
Assistant Professor
Royan Institute
Faezeh Shekari is an Assistant Professor in the Department of Stem Cells and Developmental Biology at Royan Institute (Tehran, Iran) where she oversees an extracellular vesicle (EV) research group. Faezeh is also supervisor of the EV production team in the Advanced Therapeutic Medicinal Product Center of Royan Institute, Chair of the International Society for Extracellular Vesicles (ISEV) Rigor and Standardization task force, and CEO of Celer Diagnostics (Toronto, Canada).
Steven M. Jay
Associate Professor
Fischell Department of Bioengineering at the University of Maryland
Stephen M Jay is an Associate Professor in the Fischell Department of Bioengineering at the University of Maryland (UMD; MD, USA). Steven joined UMD in 2013 following PhD training in biomedical engineering at Yale University (CT, USA) under Mark Saltzman and postdoctoral training in cardiovascular biology and molecular engineering jointly with Richard Lee at Brigham and Women’s Hospital (MA, USA) and Linda Griffith at MIT (MA, USA). His current research at UMD is focused on developing rationally designed therapeutic biotechnology based on EVs, aka exosomes. Particular issues of interest include drug loading into EVs and introducing quality control and standardization into EV biomanufacturing.
At what level are you working with exosomes?
Lisa Hamelmann (LH): Exosomes are naturally occurring cell products that are secreted by almost every cell type in the body. Due to their great potential for drug-delivery systems or disease diagnosis, there is an increasing interest in research and large-scale production of exosomes. As a cell-derived product, exosome production is dependent on cell growth. In addition to the efficient expansion of the cells, it is also important to ensure that certain behaviors and properties of the cells producing the exosomes are not changed during the upstream processes. In this regard, the environment of the cells, the cell culture medium, is an essential factor for investigating and producing exosomes. PromoCell is a trusted premier manufacturer of primary cells, including stem cells, and cell culture media systems. We design cell culture media that are specially tailored to the needs of the primary cells to ensure optimal isolation and expansion efficiency. As a certified supplier we provide various cell culture media compliant to GMP regulatory requirements and ensure the access to documentation required for exosome production in a clinical application.
Faezeh Shekari (FS): At Royan Institute, I supervise research projects about the basic science of EVs, including exosomes. Most of my research projects are focused on animal studies and in vitro evaluation of EVs therapeutic potencies. As supervisor of the EV production team in the Advanced Therapeutic Medicinal Product Center of Royan Institute, I supervise a production team to produce GMP-grade EVs for clinical trials. Moreover, I am the CEO of an EV-based diagnostics company in my home country (Firoozeh DiaTech) and a new branch in Canada (Celer Diagnostics). In this company, we developed a method to detect pathological markers in liquid biopsies with high specificity.
Steven M. Jay (SJ): I run an academic laboratory that focuses on understanding the basic biology of exosome interactions with target cells (human and prokaryotic), developing exosomes as therapeutics, and biomanufacturing of exosomes.
What are the main benefits of using exosomes and how do they compare to other therapeutics?
LH: Exosomes offer targeted, non-invasive, and efficient therapeutic approaches to a wide range of diseases and conditions. They can be engineered to carry specific payloads, such as drugs, antigens, or immune-modulatory molecules, directly to the target cells or tissue. Compared to other therapeutics, exosomes are naturally secreted by cells, so they are biosafe and have good target specificity, which leads to reduced side effects of the treatment. They also have the advantage of a surface structure that is similar to that of the cell membrane.
Additionally, exosomes can be used for non-invasive diagnostic purposes, as they can be isolated from various liquids, such as blood or urine. As they play a crucial role in tumor biology, they also offer the possibility to study cellular communication and signaling in cancer. This makes them good potential biomarkers for patient-specific tumor diagnostics or for the development of anti-cancer treatments.
FS: I use EVs for both therapeutic and diagnostic applications. I think the superiority of EVs’ therapeutic potential is laid in:
1. their lifeless nature; they cannot proliferate and they are safer than cells
2. their size; they can pass many barriers, including the blood-brain barrier
3. they can be lyophilized; therefore, they can be used as an off-the-shelf product
In the diagnostic field, I think EVs provided a breakthrough in liquid biopsy. For many many years, we searched for a needle in a haystack! And now we have a magnet to get the needle! I mean searching for a biomarker in a biological liquid such as blood is very difficult, considering the existence of highly abundant proteins that mask the detection of less abundant biomarkers. However, by EV isolation, we isolate the packages that are specifically sent by cancer cells from all the circulating noises in the blood or any other biological fluids like urine, milk or CSF.
SJ: All therapeutics have strengths and weaknesses. Exosomes are intriguing because they have some similarities to synthetic drug delivery systems but, because of their cellular origin, the power of molecular biology and genetic engineering can theoretically be applied to customize their properties. They may also have some intrinsic properties that are therapeutically beneficial, such as the ability to be preferentially taken up by specific cells or to penetrate biological barriers. Exosomes may also recapitulate the most critical benefits of some cellular therapies with a potentially superior safety profile. Exosomes also have limitations, namely that it is impossible to characterize all their components and their mechanism of action is still not clear.
What are the limitations of manufacturing and using exosomes?
LH: From our experience, one of the biggest challenges during the upstream process of exosome production is the availability and subsequent large-scale expansion of the exosome-producing cells. The first challenge is the standardized isolation of the cells from the required source, e.g., patient-derived cancer cells or MSCs. Due to the differing biological properties of exosomes secreted by different cell types, there is currently no standardized isolation. The later large-scale expansion of the cells under GMP conditions further requires standardized cell culture media from certified suppliers providing sufficient cell growth and production of pure EVs.
Looking at the regulatory side, another challenge for exosome-based therapeutics is that there is still a need for clear guidelines and standards for manufacturing, quality control and safety assessments.
FS: This is a young child! It needs time to grow. More research, rigor, and standardizations are required to pave the road through robustness as noted by the ISEV Rigor and Standardization subcommittee. I think it is too early to decide about limitations. We are still in the era of an explosion of information about EVs. We should focus on standardization and when we reach a steady state, we can talk about limitations.
SJ: There are currently no established critical quality attributes (CQAs) for exosome manufacturing. Developing reliable CQAs will be especially challenging due to the complexity of exosomes and the variability associated with any cell-based product. There is also a challenge of generating exosomes at a scale appropriate for widespread use in human at reasonable costs. Improvements in both upstream and downstream processes are still needed to enable exosomes as a practical class of therapeutics.
What should be considered when selecting media for the isolation of exosomes and do these considerations differ depending on the cell source? (for example tumor-derived exosomes versus MSC-derived exosomes)
LH: The cell culture medium is a critical factor when it comes to exosome yield, as it supports cell proliferation and expansion. Depending on the cell source the media should be optimized to support the growth and function of the specific cell type being cultured. The medium should also be optimized for high yield and purity of exosomes, while minimizing contamination with other EVs. For example, fetal bovine serum possesses several components that can interfere with endogenous EV activity and production. When choosing a medium for the expansion of the cells you either directly consider a serum- or better xeno-free medium, or, if the cells are increased to the critical levels in a serum-containing medium, they must be transferred to another medium before going into the downstream exosome production.
FS: That’s a very important issue. There are many parameters that affect cells in the culture medium including the producing cells, all the cell culture medium components, culturing conditions, and processing will impact the EVs’ biochemical composition and biological function. A task force in the Rigor and Standardization subcommittee of the ISEV is dedicated to discussing cell culture parameters that may affect EV characteristics, giving recommendations for transparent reporting, and identifying open questions. The goal of this task force is to increase awareness and promote reproducibility in EV research. The results will be published soon and will be easily accessible.
SJ: Eliminating alternative sources of exosomes in media is critical, as additives like serum can bring exosomes from their donor source along with them. Chemically-defined media is likely advantageous in the aggregate, but keeping costs down for large-scale production should also be considered.
How can exosomes be isolated on a large scale while maintaining their quality?
LH: The key word is standardization. In regard to the source of the exosomes, you should always keep in mind that healthy and high-quality cells produce high-quality therapeutic exosomes. Therefore, maintaining the quality of your cells, their functionality and the quality of their environment subsequently impacts the quality of your exosome production.
Optimal cost-efficiency, yield and standardization in large-scale exosome production may be achieved by utilizing two things; an established cell line releasing the desired exosomes and a highly defined serum-free medium. Both the cell line and the culture medium can synergize in their high intrinsic level of standardization to reproducibly yield a uniform and downstream-process-friendly exosome product of defined specification.
FS: We have a great guideline that has been written by approximately 400 experts, Minimal information for studies of EVs 2018, which is going to be updated in2023, should be considered and all criteria should be met. Briefly, besides the morphology, size distribution, and expression of protein markers, the function of EVs should be confirmed. Like the cell manufacturing process, EVs require quality control. The absence of viruses, bacteria, fungi and other unwanted bioactive components, such as, endotoxins, should be checked before any clinical study.
SJ: As long as harsh environments and methods are avoided, this should be possible. However, a key consideration is maintaining the appropriate microenvironment and phenotype of the producer cells, and this does not get enough attention. One aspect my group and some others are currently focusing on is the use of mechanical stimuli as reproducible and cheap methods to regulate producer cell behavior with respect to exosome production. But much more work needs to be done on this.
How do you see the application of exosomes evolving in the next ten years?
LH: The application of exosomes is rapidly evolving and continues to diversify, driven by advanced technologies in the production of exosomes and a better understanding of their biological functions. We already see more and more clinical trials and commercial development of exosome-based therapies as well as regulatory approvals. Given their unique biological behavior, EVs have enormous potential for use in immunotherapy and precision treatment. For example, in the field of cancer diagnosis and treatment, we already saw FDA approval for cancer diagnostic tests and promising approaches for cancer vaccine candidates. In the next ten years, the development of exosome-based diagnostic tests for early disease detection, personalized treatments and the monitoring of the response to those treatments will improve.
FS: I think the next decade will be golden because many basic issues have been resolved, and our knowledge has grown up. Many products will get approved and, specifically in the diagnostics field, I believe that we will have a revolution.
SJ: Like everything else, it depends. If the mechanism(s) of action become more well understood and biomanufacturing challenges can be solved, there is the potential for numerous exosome products to be implemented and approved within ten years. However, I think the more likely outcome is a longer trajectory, unless a “home run” type of application can be found, such as in the case of CAR T-cells for cell therapy.
Disclaimers
The opinions expressed in this interview are those of the interviewees and do not necessarily reflect the views of RegMedNet or Future Science Group.
This feature was produced in association with PromoCell.
In association with
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Posted by
on 2023-05-30
Hot-off-the-press bioink for 3D printing
The first temperature-sensitive hydrogel-based bioink has been developed for 3D printing artificial tissues.
Researchers from the Korea Institute for Science and Technology (Seoul, Korea) have developed a new bioink that does not require photocuring during the transplantation of 3D-printed tissues. This can significantly reduce the risk of unwanted side effects during this process.
Due to the increase in accidental injuries, chronic disease and a progressively aging population, there is an increased need for the transplantation of artificial organs and tissues. 3D printing technology can be used to create these 3D artificial tissues. Typically, these tissues are formed from hydrogel-based bioinks that go through a ‘hardening’ process in the body to enhance the 3D mechanical properties of the printed tissue. However, this process, known as ‘photocuring’, relies on chemical cross-linking agents and UV light to ‘set’ the 3D scaffold. This can have detrimental side effects such as causing cytotoxicity in the tissue, which damages or kills cells.
To address this issue, the researchers developed a new temperature-sensitive poly(organophosphazene) hydrogel bioink that does not require photocuring, therefore significantly lowering the risk of adverse side effects. This bioink is liquid at cool temperatures and then hardens to a hard gel consistency once it is transplanted into the body and is heated to body temperature. Further to this, it has also been designed to interact with the body’s growth factor proteins, which assist in tissue regeneration in the body. The implanted 3D scaffold creates an environment that maximizes tissue regeneration, encouraging the body to do so autonomously. This means that after a period of time, the scaffold can degrade in the body, but the tissue should continue to be regenerated via the body’s internal mechanisms.
To test this new bioink, the researchers 3D printed a scaffold using bioink that contained the growth factor proteins TGF-β1 and BMP-2, which are integral to bone regeneration. This scaffold was then transplanted into rats with damaged bones. The results showed that the surrounding tissue cells migrated into the scaffold and the bone was regenerated to normal functioning tissue. Then after 42 days, the scaffold had biodegraded away.
These were very encouraging results so the researchers hope to implement this new bioink into regenerating other tissue and organ types. “As the bioink developed this time has different physical properties, follow-up research to apply it to the regeneration of other tissues besides bone tissue is being conducted, and we expect to finally be able to commercialize bioink tailored to each tissue and organ,” commented corresponding author Song Soo-Chang.
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Posted by
on 2023-05-30
ISCT 2023: Editor’s picks
The International Society for Cell and Gene Therapy (ISCT) returns for its 29th annual meeting (31 May-3 June, Paris, France) with the theme, 'Celebrating the Progress of Advanced Therapies and Building the Future Through Translation.'
The 2022 program saw the addition of roundtable sessions and following their fantastic success ISCT has expanded and extended the roundtable program for 2023, now hosting over 50 sessions to provide a greater space for critical conversations to take place.
Read on to discover my highlights from the agenda of ISCT 2023!
Regulation: addressing global issues to improve patient access
Roundtable: Lack of Harmonization in CGT: Can We Achieve Global Convergence? (31 May, 10:45): As the field of cell and gene therapy continues to evolve, the question of whether convergence should be an objective arises. In this round table, chaired by Ilona Reischl (EMA Committee for Advanced Therapies; Austria) and Massimo Dominici (University of Modena and Reggio Emilia; Modena, Italy), panelists will discuss the harmonization of cell and gene therapy, focusing on aspects such as nomenclature, regulation and GMP manufacturing.
Roundtable: How will the EU SoHO Regulation Impact Your Cell Collection? (31 May, 13:00): Explore how the European Commission’s proposal for a regulation on the safety and quality of substances of human origin (SoHO) will impact the collection of blood, tissue and cells in Europe and the resulting implications for advanced therapy medicinal products.
Manufacturing: overcoming bottlenecks to meet increasing demands
Roundtable: Point-of-Care Manufacturing: Disrupting & Decentralizing Autologous Delivery (31 May, 14:15): Is point-of-care manufacturing the best near-term solution to overcome the challenge of commercial patient access? Patrick Rivers (Aquilo Capital; CA, USA) will lead discussions on the regulatory considerations, barriers to broad adoption and the feasibility of establishing point-of-care manufacturing.
Concurrent Session: Required infrastructure for manufacturing advanced therapy products at mass scale (June 2, 15:45): How can product and process developers, and manufacturing and commercialization specialists prepare for the ever-increasing demand for cell and gene therapies?
Clinical Translation: navigating the path from bench to bedside
Concurrent Session: Allogeneic vs Autologous Debate - Developing Cell Therapies with an Eye to Patient Access (2 June, 08:00): Julie Allickson (Mayo Clinic; MN, USA) and Bruce Levine (University of Pennsylvania; PA, USA) will be joined by experts from across the industry to share their perspectives on whether the success of allogeneic CAR-T cell therapies reflects the potential of the field.
Concurrent Session: Challenges in Cell Therapy for Solid Tumors (2 June, 9:15): Is a breakthrough for cancer treatment on the horizon? Although cell therapies have had some success in the treatment of hematological malignancies, solid tumors remain a challenge. This session will discuss the various possible approaches to address this issue.
Workforce development: closing the talent gap
Roundtable: Elevating the CGT Workforce in Europe - Challenges, Opportunities, and Educational Approaches (3 June, 10:15)
Roundtable: Retaining the CGT Workforce: How NOT to Lose a Technician in 10 Days (June 3, 11.45)
Asia Pacific Sessions: navigating the market
Roundtable: Maximizing CGT product value - Why you shouldn’t overlook APAC (3 June, 9:00)
Roundtable: Market Access and Reimbursement: Same Problem, Different Region (3 June, 10:15)
Let us know what you are looking forward to by tweeting us @RegMedNet, or leave a comment on Facebook or LinkedIn!
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on 2023-05-29
The best things come in small packages: new ‘mini gene’ therapy for Usher F1
New mini gene therapy could successfully restore hearing and sight to those who suffer from Usher 1F.
A recent paper from researchers at Harvard Medical School (MA, USA) has proposed a new ‘mini gene’ therapy to fix the DNA mutation that leads to both sight and hearing loss in people suffering from the genetic disease Usher syndrome type 1F.
There are currently no treatments for Usher 1F, a genetic disorder where children are typically born profoundly deaf, have poor balance and progressively lose their sight until they become totally blind by the time they reach adulthood. The coupled progressive deterioration of sight and hearing is thought to be due to a mutation of the gene that codes for the protein protocadherin-15, which has a slightly different role in each sense but is vital for both to function correctly.
The research team had previously established that protocadherin-15 combines with another protein called ‘cadherin 23’ in the hair cells of the inner ear to create filamentous structures that mechanically open ion channels when sound waves cause vibrations in the inner ear. The opening of these ion channels allows the electrical impulses to be sent to the brain and be detected as sound. When protocadherin 15 is not produced due to genetic mutations, these signals cannot enter the hair cells, preventing sound waves from being converted to electrical signals and ultimately rendering the patient deaf.
To fix this issue, co-senior author David Corey proposed a gene therapy approach to deliver the gene for protocadherin 15 to the hair cells. However, the genetic code for the protein is too big to fit in the viral capsules typically used for gene therapy. Therefore, the researchers had to find a way of reducing the DNA code to a suitable size while still being able to code correctly for the protein.
First, the team enlisted the help of co-senior author Marcos Sotomayor (Ohio State University, OH, USA) to map all 25,000 atoms of protocadherin 15 protein using x-ray crystallography and a cryo-electron microscope. Sotomayor revealed that the protein is structured to form 11 links in a chain with a binding region at one end that connects to cadherin 23.
With the protein structure understood, Sotomayor created a panel of eight truncated versions of the protein where between 3-5 of the 11 links were removed. These protein variants were then reverse-engineered to acquire the genetic code required to produce each of them. These “mini genes” were then tested in inner ear cells in vitro to validate that they still bound to cadherin 23 and retained their function. Of the eight mini genes, three were small enough to fit inside a viral capsid and so were selected for the next stage of the experiment.
Using mice that had been genetically modified to not produce protocadherin 15 each of the three mini genes was tested to evaluate their performance. There only one mini gene Was able to successfully produce a protein in vivo that was able to bind with cadherin 23 and open the ion channels, allowing electrical signals to be transported to the brain. Further auditory testing showed that the previously deaf mice could now hear.
These are very promising results; however, the ultimate goal for this research team isn’t to fix deafness in Usher syndrome sufferers but rather to prevent blindness, “the whole project was designed to study the ear with the idea that something that works in the ear can later be applied to the eye, as an article of faith…While the best test system is the mouse inner ear, the immediate goal is a treatment for blindness,” noted Coney.
The reasons for this are twofold. Usher 1F patients are born totally deaf and may lack hair cells, likely preventing this gene therapy from yielding much success, while the blindness is a slow onset, providing a bigger window of opportunity to correct the condition and prevent patients losing their sight. Furthermore, cochlear implants can partially resolve the deafness, while there is no treatment to protect their sight.
The team initially focused on the use of this gene therapy to restore hearing for logistical reasons. The immediate hearing loss, when compared to the slow onset blindness allowed the mini genes to be tested in much more rapidly established mouse models with a more immediate readout. This allowed the team to establish that the mini gene could successfully be used to code for a functional protein in vivo before starting on the issue of fixing sight.
The team is now testing the mini genes in the eyes of zebrafish, which experience more rapid vision loss when protocadherin 15 is knocked out in the retina providing results faster than a mouse model. The research group hopes that if these trials with zebrafish are successful, they can start using it to treat blindness in primates and eventually humans.
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on 2023-05-26
ISCT: a pre-conference interview with Jacques Galipeau
In advance of the International Society for Cell and Gene Therapy 2023 annual meeting (ISCT; 31 May-3 June; Paris, France), we spoke with Jacques Galipeau about what we can look forward to, how ISCT has expanded their roundtable plans from last year, and the developments that we can expect to see from the ISCT in the next year.
Please introduce yourself and give an overview of your role.
I am a practicing Hematologist and the Don and Marilyn Anderson Professor of Oncology at the University of Wisconsin-Madison (WI, USA), where I'm also Associate Dean for Therapeutics Development at the School of Medicine and I am the current President of the International Society of Cell Therapy (ISCT; Canada) with my mandate being from 2022 to 2024.
Which talk or session are you most looking forward to at the ISCT annual meeting?
Like a kid in a candy store! I’m not sure where to start. I very much look forward to the roundtables, which we added to the program last year for the first time, as they give the opportunity to be part of live conversations with thought leaders. Of course, the plenaries are a must-see. It’s going to be exciting to hear thought leaders speak to hot-button issues in the moment and, of course, have the opportunity to network.
This year’s program has a large focus on translation to the clinic. Can you give us a brief overview of the biggest challenges facing the translation of advanced therapies?
With cell-based therapies, you have all the complexities of dealing with a living therapeutic. The challenges right now are primarily in logistics and they were really highlighted during the COVID-19 pandemic. You have to consider things such as point-of-care manufacturing versus shipping these living therapeutics to the patient. And while we’ve been doing bone marrow transplants for the past 50 years, and we've been shipping cells around the world for the past quarter century, those cells are minimally manipulated and, therefore, in a way, they are quite forgiving. In comparison, genetically enhanced cells have been traumatized, making them much more delicate to ship.
There is also the regulatory and quality assurance aspect, which is trying to catch up. As soon as you change the characteristics of the cells, for example, by genetically manipulating them, the therapeutic is now regulated like a drug. And employing this regulatory template for living therapeutics doesn’t work very well. The living therapeutics we've been dealing with in medicine for a long time ̶ kidney transplant, cornea transplant, bone marrow transplant etc., ̶ aren’t regulated like drugs. But cell therapies are. There is also a lot of heterogeneity between the different regulatory environments internationally.
What is the main message you would like attendees to take away from the conference with regard to translation?
Well, from a translation perspective, 10 years ago the considerations of translation were all theoretical. But now they are reality-based and occurring in real time.
The message I would like to convey to our attendees is that I feel that the old rules that applied for medicinal chemistry are maladapted for the deployment of living therapeutics. So, I would invite people to have a fresh perspective rather than being tied up by the rules and trying to navigate them. I think we need to be bold and present novel, creative, practical remedies for the sustainable deployment of these technologies.
ISCT 2022 saw the addition of roundtable sessions to the program for the first time. What benefits did you see from this and how are roundtables being included in this year’s program?
It's a format we beta-tested last year in San Francisco; it was a gigantic hit. It's really the absence of scripting that makes it so attractive. You can get really engaged audience participation and it gives greater space for critical conversations to take place. It's an exciting time in the industry because things are growing and we don't know what we don't know. That's the beautiful thing about where we are in our space ̶ it's uncharted territory and nothing is set in stone.
What developments can we expect to see from the ISCT in the next year?
A huge initiative from ISCT is focusing on workforce development. Due to the Cambrian explosion we’ve seen in the development of novel living therapeutics there is a great need for expertise, for example, in the cell processing, regulatory environment, quality assurance, discovery, post-marketing approval, tracking, etc., I could go on forever really. We at the ISCT are positioned to be thought leaders in the cell and gene therapy space and we have a long track record of excelling at knowledge transfer. So now we can leverage those things to provide useful, practical materials for workforce development.
Disclaimer
The opinions expressed in this interview are those of the interviewees and do not necessarily reflect the views of RegMedNet or Future Science Group.
The post ISCT: a pre-conference interview with Jacques Galipeau appeared first on RegMedNet.
Posted by
on 2023-05-26
Cell therapy weekly: uBriGene moves into the US market with GMP facility acquisition
This week: UBriGene (Vancouver, Canada) moves into the US market with the acquisition of a GMP facility in Boston, Massachusetts; Therapeutic Solutions International (CA, USA) creates a subsidiary company to commercialize JadiCell and ElevateBio (MA, USA) secures US$401 million in Series D funding.
The news highlights:
UBriGene moves into the US market with GMP facility acquisition
Spin-off will commercialize JadiCell
ElevateBio to accelerate growth with US$ 401 million
UBriGene moves into the US market with GMP facility acquisition
The cell and gene therapy contract development and manufacturing organization (CDMO), uBriGene (Vancouver, Canada), has expanded into the US market through its acquisition of a state-of-the-art multiproduct GMP manufacturing facility from Mustang Bio (MA, USA). The site is based in Worcester, Boston, Massachusetts, and is the company’s first facility in the US. The company currently has two other GMP facilities in China and its headquarters in Vancouver, Canada. Clinical manufacturing of Mustang Bio's CAR-T cell therapy, MB-106, will be taken over by uBriGene as part of the purchase.
Alex Chen, President of uBriGene, stated: “This acquisition is important to uBriGene’s commitment to support the development, clinical, and commercial supply of cell and gene therapies to meet rapidly growing demand. We hope to work together with the University of Massachusetts Medical School to continue to grow the advanced therapy manufacturing ecosystem in the Worcester region.”
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Spin-off will commercialize JadiCell
Therapeutic Solutions International (CA, USA) has created a subsidiary company, CTE Biologics, dedicated to the commercialization of JadiCell for the treatment of chronic traumatic encephalopathy. JadiCells are mesenchymal stem cells obtained from the lining of the umbilical cord and they have been licensed by Therapeutic Solutions International for this indication since 2019. The company is presently addressing questions from the US FDA before clinical trials are initiated.
“Based on our preclinical and pilot clinical observations we believe that our approach to Chronic Traumatic Encephalopathy possesses potential to address a condition which currently is not even properly diagnosed in living patients,” said Timothy Dixon, President, and CEO of Therapeutic Solutions International. “Creation of CTE Biologics allows for specialization and focus while leveraging existing resources within Therapeutic Solutions International.”
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ElevateBio to accelerate growth with US$ 401 million
ElevateBio (MA, USA) announced the closing of its Series D funding, reaching US$401 million. The financing was led by the AyurMaya Capital Management Fund (MA, USA), which is managed by Matrix Capital Management (MA, USA). ElevateBio will utilize the funding to support and advance its technology platforms, including gene editing, iPSC and RNA, cell protein and vector engineering, as well as the company’s end-to-end genetic medicine current Good Manufacturing Practice manufacturing and process development business, BaseCamp®.
“We have made significant strides in scaling our technologies and end-to-end capabilities in our pursuit to become the world’s most indispensable cell and gene therapy technology company. We are thrilled to welcome Khalil to our Board as his expertise will be invaluable as the number of strategic partners harnessing the power of our integrated ecosystem continues to grow,” said David Hallal, Chairman and Chief Executive Officer of ElevateBio. “We’re emboldened by the pace of advancements to our technology platforms and continue to drive innovation from concept through commercialization and redefine how companies operate, how products are created, and how disease is treated.”
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The post Cell therapy weekly: uBriGene moves into the US market with GMP facility acquisition appeared first on RegMedNet.
Posted by
on 2023-05-25
