March 2024
From April 2024 going forward, issues of The Vector are only available to current ASGCT members. Join the Society to access this and other benefits!
Editorial Team
Jon Brudvig, PhD – Editor, The Vector
Jessica Schneller, PhD – Associate Editor, The Vector
Wan Du, MD, 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
Plan Your Annual Meeting Schedule with Session Paths
Hello ASGCT members,
We’re officially less than two months away from the 27th Annual Meeting in Baltimore! The meeting will be here before we know it, so make sure you’re registered to attend and your hotel room is booked before the ASGCT room block sells out. While the block closes on April 8, it is already nearly sold out, so book your room as soon as you can! Hotel reservations must be booked and managed through your meeting registration and you must be registered to book a room.
Once you’ve taken care of those logistics, start planning your time at the meeting with our interactive program and our new session paths pages! We’ve broken the meeting down into six focus areas to help you navigate your way through each day of the meeting depending on what you’d like to learn. Whether you’re a first-time attendee (welcome!), a clinician, or interested in areas like CGT for cancer or gene editing, we offer session recommendations for every time block to keep you busy.
Finally, speaking of new offerings at the meeting, you can claim CME credits for one of our workshops on the first day! Attend the in-person only workshop, Revolutionizing Care: Gene Therapy Unveiled for Clinicians, and receive a maximum of four AMA PRA Category 1 credits.™ Jointly sponsored by ASGCT and the University of Massachusetts Chan Medical School, the workshop seeks to establish baseline education and highlight emerging trends in the biology, toxicity, and administration of CGT products for healthcare professionals from diverse backgrounds.
I look forward to seeing many of you in Baltimore!
Jeffrey S. Chamberlain, PhD
ASGCT President
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Breaking Through
High-dose systemic adeno-associated virus vector administration causes liver and sinusoidal endothelial cell injury
Hordeaux J, Lamontagne RJ, Song C, Buchlis G, Dyer C, Buza EL, Ramezani A, Wielechowski E, Greig JA, Chichester JA, Bell P & Wilson JM
DOI: https://doi.org/10.1016/j.ymthe.2024.02.002
Summary by Jon Brudvig, PhD
AAV gene therapies have been massively successful for the treatment of several systemic diseases. For some indications, however, efficacy has been hindered by dose-limiting toxicities that prevent delivery of a dose that reaches adequate numbers of target cells. This has hindered the development of therapies for diseases such as Duchenne muscular dystrophy, where high AAV doses have caused serious adverse events including patient deaths. While there are common clinical findings across many cases of AAV‑induced acute toxicity (i.e., elevated liver enzymes, thrombocytopenia, thrombotic microangiopathy), the underlying etiology has remained elusive. In the April issue of Molecular Therapy, Juliette Hordeaux and colleagues present compelling analyses from extensive nonhuman primate (NHP) studies involving n=46 animals, ultimately finding that acute toxicity manifests from high-level transduction and subsequent expression‑induced burden in several key liver cell types, most notably in liver sinusoidal endothelial cells (LSECs).
To investigate mechanisms of liver and endothelial cell injury, Hordeaux et al. analyzed retrospective data and samples from several existing studies conducted at the gene therapy program at the University of Pennsylvania, all conducted using high doses (~1e14 GC/kg) of AAV Clade F vectors expressing therapeutic transgenes from ubiquitously expressed promoters. In parallel, the authors conducted prospective high-dose studies in n=10 NHPs using a similar vector expressing enhanced green fluorescent protein (eGFP). Out of the total n=46 animals, five showed severe symptoms of acute toxicity and were euthanized early. All five of these animals presented with elevated liver enzymes, and all but one exhibited thrombocytopenia (low platelet count). Histopathological examination revealed extensive hepatocellular degeneration, microthrombi and LSEC injury.
Importantly, these observations occurred in the days immediately following AAV dosing, with an apparent peak on day 3. While there was some later evidence of complement activation and adaptive immunity, the relative timing of immune responses suggested that they were not responsible for the early patterns of injury. Instead, high-level transduction and expression in hepatocytes and LSECs seemed to blame, as supported by single cell RNAseq data. Hepatocytes and LSECs broadly expressed high levels of GFP and displayed altered patterns of gene expression suggestive of injury and dysregulation of cell identity, with a peak temporally coinciding with pathological observations. Other recent studies have also supported the notion that high AAV expression in transduced cells causes cell injury manifesting in acute toxicity. For example, “promoterless” vectors dosed in one study lacked the characteristic patterns of liver injury observed for other AAV9 vectors.
Collectively, these recent studies are converging on a model wherein high-dose AAV9 and related AAV vectors transduce multiple liver cell populations with great efficiency, leading to expression-induced stress and subsequent inflammation and cell degeneration. Now that the problem has been defined, engineering strategies will surely be pursued to overcome this obstacle. Liver-detargeted capsids could shift expression towards a more balanced systemic population of cells, or alternatively, cassette-based strategies could utilize liver-exclusive promoters or microRNA-mediated detargeting. If such strategies are successful, higher-dose, safer AAV therapies could soon expand the list of indications that are amenable to treatment.
From Molecular Therapy
On the Molecular Therapy Podcast: Drs. David Schaffer and Adam Schieferecke to discuss a recent article they published with colleagues in the February issue of Molecular Therapy titled, Evolving membrane-associated accessory protein variants for improved adeno-associated virus production.
Active Calls for Papers
RNA and epigenetic editing: A new generation of precision therapeutics
Novel therapeutic targets and biomarker development
Latest MT issues: Check out the most recent issues of these Molecular Therapy family journals:
Society News
Renew Your Membership by Friday, March 15
This Friday, March 15 is the final day to renew your ASGCT membership for 2024! Maintain accesss to exclusive benefits like your Molecular Therapy subscription, registration discounts for the Annual Meeting and other events, grant and award eligibility, and more!
Subscribe to the ASGCT Podcast Network
Did you know you can listen and subscribe to three shows on our podcast network? Hear from CGT experts during one-on-one interviews about impactful research, pressing challenges, and personal career journeys. Subscribe on Apple and Spotify!
Use Free Services from National Gene Vector Biorepository
The National Gene Vector Biorepository (NGVB), now in its 16th year, benefits qualified NHLBI investigators at all stages of clinical development and offers free services like reagents, cell lines, and archiving. Learn more about the NGVB on our blog.
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.
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Public Policy
Watch Dr. Terence Flotte's Testimony Before U.S. House Subcommittee
On February 29, ASGCT’s Vice President, Dr. Terence Flotte, testified before the Energy and Commerce Subcommittee on Health in a hearing titled “Legislative Proposals to Support Patients with Rare Diseases.” The Society appreciated the opportunity to represent the CGT field on Rare Disease Day.
Dr. Flotte shared insights on the challenges and opportunities in advancing CGT development for rare diseases. A majority of rare diseases are genetic in origin; Dr. Flotte explained how CGTs are uniquely situated to address these types of conditions. Flotte also emphasized the urgency in addressing access barriers for patients with rare diseases from preclinical research through commercialization. He highlighted the critical need for proactive policies to enable CGT development. His testimony underscored the importance of collaboration among stakeholders and the necessity for a flexible regulatory framework to expedite safe and effective treatments for the most vulnerable patient populations.
A full blog post detailing Dr. Flotte’s testimony is available here.
FDA Liaison Meeting Presentations Focus on AAV + Genome Editing
ASGCT held its sixth annual FDA Liaison Meeting on February 23. Society members gave two presentations to FDA on significant topics in the field, followed by a presentation from Dr. Nicole Verdun, Director of CBER”s Office of Therapeutic Products (OTP). View the full summary of the event along with ASGCT’s and FDA’s slide presentations.
The Society’s first presentation to FDA, Class Considerations for Determining Safety and Efficacy Outcomes for AAV Gene Therapies, focused on safety and efficacy for AAV gene therapies. A key theme was the need to bring the field together to resolve questions and work toward FDA guidance on vital aspects such as immunogenicity and integration. The second ASGCT presentation discussed On- and Off-target Analysis for Genome Editing. Presenters addressed considerations for on-target analysis, a case study on biological de-risking, and CMC considerations.
Dr. Verdun then presented staffing updates for the OTP super-office. She also touched on her vision for the office, and discussed the various pilot programs that aim to accelerate development. Dr. Verdun reviewed the START Pilot, RDEA Program, CoGenT International Pilot, and forthcoming Platform Technologies Designation. The director and staff also engaged with the Society on the CRDP Pilot Program.
These Liaison Meetings serve as a key communication point between ASGCT members and the Agency reviewers. ASGCT appreciates FDA’s candor and willingness to come together to discuss these complex issues.
Society Weighs in on Advanced Manufacturing for CGT
The Society submitted comments on the Advanced Manufacturing Technologies (AMT) Designation Program draft guidance. While the pipeline of cell and gene therapies (CGTs) has been growing exponentially, the adoption of advanced manufacturing practices leveraging novel technologies has been slow. Traditionally, the FDA has provided binding feedback about manufacturing technologies during a biologics license application (BLA). This creates uncertainty for product sponsors who would need to make costly manufacturing changes to leverage a novel technology - while running the risk that it may not be approved by the FDA. The AMT pathway, mandated by Congress, would decouple the product from the advanced manufacturing technology and expedite applications with a designated AMT.
ASGCT’s response noted the creation of a product agnostic pathway is an important step toward the adoption of new manufacturing technologies. If implemented properly, the AMT Designation Program could help address the challenges currently facing the manufacturers and sponsors of CGTs, as there is a current imbalance in how CDER and CBER products are treated in the assessment of manufacturing. Current FDA policy does not allow a BLA to incorporate information about drug substance, drug intermediate or drug product through referencing a drug master file (DMF). DMFs are the main way that propriety information from contract manufacturers, or other third parties, can be shared with the Agency without having to disclose it to a drug sponsor. Recently, FDA finalized a rule that codified this practice in regulation.
Be sure to check out our new blog post for more specifics on ASGCT’s comments. The Society is excited to see the Agency tackling one of the biggest bottlenecks in CGT development – the manufacturing process – and will continue to update on activity in this space.
FDA Incorporates ASGCT Recommendations in Final Guidances
ASGCT recently contributed to positive changes in FDA’s regulation of two genetic therapy modalities. In 2022 the Society commented on two draft guidances that have now been finalized; we are pleased to see FDA incorporate many of ASGCT’s recommendations in the final versions of those two guidances. While a full comparison is available online, in summary:
Human Gene Therapy Products Incorporating Human Genome Editing
Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products
The Agency hosted webinars for each of these new releases to discuss key considerations in the final guidances. Recordings of the sessions on genome editing and CAR Ts are now available.
FDA’s Center for Biologics Evaluation and Research (CBER) has published also published their full 2024 Guidance Agenda. This outlines the guidance documents the Agency plans to release in 2024 and indicates their regulatory priorities for the coming year. The Society is especially watching for the release of two new draft guidances required under the Food and Drug Omnibus Report Act (FDORA) of 2022: one governing a new Platform Technologies Designation, and another on diversity action plan guidances. ASGCT is currently working on a response to the recently-released Potency Assurance for CGT Products draft guidance.
New CGT Payment Model Could Expand Access to Therapies
The Biden-Harris Administration unveiled details regarding the timeline and implementation of the Cell and Gene Therapy (CGT) Access Model. Announced on January 30, the model would enable the Centers for Medicare and Medicaid Services (CMS) to negotiate outcomes-based agreements (OBAs) with manufacturers, with a focus on CGT treatments for sickle cell disease (SCD). Notably, this follows FDA's recent approval of two gene therapies, Casgevy and Lyfgenia, for SCD patients aged 12 and older. SCD disproportionately affects Black Americans and has significant associated healthcare costs for the estimated 100,000 affected individuals in the United States. ASGCT is tracking the initiative closely; if implemented properly, it could help expand access to innovative, life-saving gene therapies.
The model is structured to involve CMS, states, and manufacturers, and is voluntary. CMS has indicated that states and select territories can begin submitting their non-binding letters of intent to participate in the model as early as April. In March, CMS will release a request for application, and manufacturers will have the option to participate. Negotiations with manufacturers on outcomes-based agreements are expected to begin in May and go through November, with an expected launch in January 2025.
As stakeholders navigate the implementation process, ongoing engagement and collaboration will be essential to realize the model's full potential to advance patient care and address unmet medical needs.
Industry News
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