The Vector
Volume 11, Issue 7: July 2022
Editorial Team
Edith Pfister, PhD – Editor, The Vector
Karen Bulaklak, PhD – Associate Editor, The Vector
Jon Brudvig, PhD – Junior Editor, The Vector
Inside This Issue
Leadership Message
Breaking Through
From Molecular Therapy
Society News
Career Center
Public Policy
Industry News
Leadership Message
Final Weeks to Apply for Award Funding, Attend the ASGCT-ISSCR Symposium
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Hello ASGCT Members,
I hope you’re all enjoying the summer. Back when I was ASGCT president, the summers were a slower time for programming and events, but I’m happy to tell you that’s no longer the case. Since we have more initiatives than ever before, I want to tell you about a few opportunities from ASGCT that I hope you’ll take advantage of in the coming weeks.
ASGCT is accepting applications for Career Development Awards (CDAs) and Diversity, Equity, & Inclusion (DEI) Awards through Aug. 1. Members can apply for one of six $100,000 CDA awards, which are meant to support independent transformative pilot studies in gene and cell therapy. ASGCT is also offering three DEI awards totaling $250,000 for members from underrepresented minority populations, underrepresented groups in the scientific workforce, and members conducting research on conditions that disproportionately affect minorities. Receiving an ASGCT award is an incredible honor, and I encourage you to learn more here and apply by Aug. 1.
In September, we have two excellent events happening in back-to-back weeks. As an ASGCT member, you can receive a discount if you’re interested in attending the ASGCT/ISSCR international symposium, Emerging Therapies at the Intersection of Genetic and Cellular Technologies. The meeting will highlight groundbreaking work developing therapies for diseases of the nervous, hematopoietic, and muscle systems, diabetes, metabolic diseases, and cancer, and feature forward-looking new technologies shaping the future of the field. I’ll be giving a keynote talk during the event Sept. 21-23, so I hope to see you either in person in the city of my medical school alma mater, Madison, WI, or virtually.
Registration is now open for our fourth annual Policy Summit—also a hybrid event—in Washington, D.C. Sept. 26-27. Speakers will discuss hot topics that inform policies impacting the field, like PDUFA reauthorization, diversity in clinical trials, and more. The agenda will be updated as speakers are confirmed.
Take care and be well,
Donald B. Kohn, MD
ASGCT Past President
Breaking Through
Base-edited cynomolgus monkeys mimic core symptoms ofSTXBP1 encephalopathy
Lu Z, He S, Jiang J, Zhuang L, Wang Y, Yang G, Jiang X, Nie Y, Fu J, Zhang X, Lu Y, Bian X, Chang HC, Xiong Z, Huang X, Liu Z and Sun Q
DOI: https://doi.org/10.1016/j.ymthe.2022.03.001
Summary by Jon Brudvig, PhD
While genetically altered mice have become a mainstay for disease modeling, many human diseases have proven difficult to model in this species. Complex CNS disorders, in particular, often fail to translate between humans and mice, likely due to differences in brain anatomy and connectivity. In a recent Molecular Therapy article, Lu et al. present one potential solution to this problem by generating the first base-edited nonhuman primate model of a human disease.
STXBP1 encephalopathy is a severe early-onset disorder characterized by intractable seizures and intellectual disability. Caused by heterozygous (or rarely, homozygous) mutations in STXBP1, which encodes a protein essential for neurotransmitter release, STXBP1 encephalopathy has no disease-modifying therapy or cure. Transgenic mouse models of the disease have yielded important insights into cellular mechanisms of disease, but exhibit several key differences with human patients that have limited their utility for therapeutic development. Namely, STXBP1 mouse models fail to recapitulate common electroencephalogram (EEG) seizure patterns and respond well to seizure treatment with levetiracetam, a drug which is ineffective in many STXBP1 patients. The researchers here hypothesized that a nonhuman primate model with a brain architecture more similar to humans could better recapitulate clinical phenotypes.
To develop their model, the authors used base editing, a newer iteration of CRISPR in which an engineered Cas9 is used to generate precise single-base DNA edits. Single-cell cynomolgus monkey embryos were injected with a cytosine base editor and guide RNAs that directed a single-base edit mirroring a common pathogenic variant, R292H. The gene-edited embryos were then transplanted into surrogate monkeys, yielding two live births. Both gene-edited monkeys possessed the R292H mutation at a frequency of approximately 50%, indicative of a heterozygous condition. Several fetuses with homozygous mutations did not survive until term.
The live born monkeys both exhibited severe seizures with EEG patterns consistent with those observed in STXBP1 patients and biochemical defects that mirrored those observed in STXBP1 mice. Importantly, the seizures were not treatable with levetiracetam, demonstrating the enhanced translatability of the model. The authors also leveraged the model’s human-like brain architecture to explore the developmental impacts of STXBP1 haploinsufficiency, finding depletion of a unique subset of excitatory neurons reflecting a previously unreported component of disease etiology.
It remains to be seen whether models like this one will lead to breakthroughs in the treatment of genetic diseases, but the obvious translational value suggests great potential. In addition to more faithfully modeling complex human diseases that fail to manifest in mice, nonhuman primate models could also offer important benefits for testing genetic therapies. Adeno-associated viruses (AAVs), for example, exhibit vastly different transduction patterns in rodents and primates, and testing in nonhuman primate models of disease could therefore offer better predictions of efficacy and more accurate dose selection for candidate AAV therapies.
From Molecular Therapy
Call for papers: Exploiting extracellular vesicles as therapeutic agents
The editors of the Molecular Therapy family of journals are pleased to announce a concomitant series of special issues across the journal family focused on the identification, characterization, and standardization of EV technology and the exploitation of the latter as therapeutic agents and biomarkers for the treatment of the gamut of human disease. Learn more.
Latest MT issues: Check out the most recent issues of these Molecular Therapy family journals:
Society News
Last Chance to Apply for Nearly $1 Million in Career Development, DEI Awards
There's still time to apply for 2022 award funding! ASGCT Members working toward independence in their gene and cell therapy careers are eligible for one of six $100,000 Career Development Awards. Three more Members from underrepresented minority populations or groups in the scientific workforce, or those conducting research for conditions disproportionately affecting minorities, can apply for Diversity, Equity, and Inclusion Awards. Apply by August 1!
Free Tomorrow: Introduction to GMP Regulations
This month’s café will focus on Good Manufacturing Practices (GMPs). While these regulations are governed by the FDA, their applications to the field of gene and cell therapy are still being developed. Our café will begin with an introduction from Gautam Ranade, followed by presentations from Jasna Curak and Stephan Croft.Register for free and bring your questions for a one-hour Q&A!
Dive into Preclinical Studies on July 28
Register for free for our next Patient Education Lunch & Learn! Speakers will review models for preclinical studies, the process behind generating sufficient efficacy & safety data, how patient advocates can help, and more.
Career Center
Are you looking for a job in the field of gene and cell therapy? Check out the new ASGCT Career Center for great opportunities with industry, government, and academic organizations. Sign up to receive alerts for open jobs in your area.
If you're from a recruiting institution, advertise in the Featured Jobs section to target the 4,000+ audience of The Vector.
Featured Jobs
Public Policy
Hear from Keynote Speaker John Coster, PhD, at the Policy Summit
Registration for the hybrid 2022 Policy Summit is now open! Join us September 26-27 in Washington D.C. or virtually as presenters dive into key issues in the field including coverage and reimbursement, accelerated approval, diversity in CGT, and the upcoming PDUFA VII reauthorization. In-person attendance will be capped, so be sure to register soon to reserve your spot. This year’s sessions will be a mix of traditional presentations and interactive roundtable discussions to allow for maximum engagement with speakers and the audience.
ASGCT is excited to announce Dr. John Coster as our keynote speaker at this year’s Policy Summit. Dr. Coster currently serves as the director of the division of pharmacy at the Center for Medicaid and CHIP Services (CMCS). He will be offering his perspective on the Biden administration’s priorities for Medicaid coverage of gene and cell therapies.
Whether it's in D.C. or online, we hope you’ll join us! An agenda is available on our website and will be updated as new speakers are confirmed.
Society Submits Comments to FDA on Clinical Trial Diversity, CAR T Manufacturing
ASGCT’s Policy and Advocacy team has been in the thick of this regulatory cycle, submitting five sets of comments on CGT regulation and reimbursement since last month.
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ASGCT submitted comments to FDA on the draft guidance Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products. ASGCT emphasized the need to balance defined baseline expectations for sponsors with the flexibility to evaluate data for individual development programs based upon the benefit-risk of unmet medical need and the condition being treated. Comments also addressed CMC considerations for cell therapies.
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In comments to FDA on the draft guidance Human Gene Therapy Products Incorporating Human Genome Editing, ASGCT similarly expressed that the guidance was broadly appropriate, and was encouraged to see this dedicated attention from FDA as GE research and development expands, while asking for clarification or additional information on key details. Clarity was requested from the agency on the use of surrogate endpoints and accelerated approval for GE products. The Society also stressed that rapid innovation in the GE field warrants a CMC framework that remains flexible, risk-based, and correlated with the extent of clinical experience.
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The Society supported FDA’s efforts to improve enrollment of historically underrepresented populations in clinical research and recognized the issuance of the draft guidance Diversity Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Trials. More representative clinical trial populations are essential to properly understanding and evaluating the benefit-risk profile of innovative medical products, specifically cell and gene therapy products. ASGCT highlights the timing of the issuance of this draft guidance and notes that its issuance parallels similar legislative efforts in Congress.
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ASGCT submitted comments on proposed updates to the federal Screening Framework Guidance for Providers of Synthetic Double-Stranded DNA guidance. ASGCT addressed concerns about screening length of RNAs for biosecurity, streamlining data sharing when appropriate, and additional preemptive purchasing requirements.
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The Center for Medicare and Medicaid Services (CMS) solicited comments for the FY23 Inpatient Prospective Payment Systems Proposed Rule. ASGCT urged CMS to consider a new reimbursement methodology that establishes separate payment for low-volume, high-cost drugs. In addition, the Society recommended a reform to the New Technology Add-On Payment (NTAP) system to accommodate this new wave of technologies. Through this dialogue ASGCT hopes to ensure patient access is not hindered by inefficient or outdated payment systems.
FDA User Fee Reauthorization Moves Through Congress
Last month saw lots of movement in Congress as the Prescription Drug User Fee Authorization Act (PDUFA) deadline looms. On June 8, the House of Representatives passed their version of the FDA user fee package (HR7667), including PDUFA, with a solid bipartisan vote (392-28). This version is now being combined with the Senate version, the FDA Safety and Landmark Advancements Act (FDASLA). While both chambers have indicated a desire to close out this process before Congress leaves town for its annual August recess, the final vote could be held up until Congress returns in September. For more background on the differences between the bills and information about the PDUFA process, read this post our blog.
ASGCT has been active throughout the PDUFA process and has submitted comments for the 2020 public meeting and 2021 commitment letter. The PDUFA VII authorization negotiations are a culmination of many of the big picture issues facing the gene therapy field. These include enhancing and streamlining communications with the Agency, expanding guidance for cell and gene therapy development, and focusing on the unique attributes of CGT CMC data. To hear more about these issues in depth, and to learn more about the provisions included in PDUFA VII, be sure to check out our Policy Summit session on the reauthorization process.