December 2023
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
TITLE HERE
Hello ASGCT Members,
I can’t believe we’re already at the end of another fantastic year! As a professional in this field, there is a lot to be proud of and even more to look forward to in the future. Just last week, we saw the landmark approval of the first two gene therapies to treat sickle cell disease in the U.S., including the first-approved therapy in the U.S. that uses CRISPR. In addition to historic gene therapy approvals earlier this year for hemophilia A, Duchenne muscular dystrophy, and dystrophic epidermolysis bullosa, last week’s news was an incredible way to wrap up 2023.
I’m extremely thankful to all of you for your membership in ASGCT. Without our members, we could not have put together our largest-ever Annual Meeting, organized the inaugural Spotlight on Immuno-Oncology Conference, provided more award funding than ever before, created more international opportunities and patient resources, and so much more. I hope you’ll join me and renew your membership so that you can maintain access to our current and future programming. We have big plans for 2024 and I don’t want you to miss the opportunity to be part of it! Renew today to stay in the loop.
After you renew your membership, register early for the 27th Annual Meeting! We’ll be back on the East Coast in Baltimore, MD, May 7-11, 2024 and I encourage you to secure your spot to receive early-bird rates. We’ll hear from an excellent group of keynote speakers: Kevin Campbell, PhD; Charles Murry, MD, PhD; Beverly Davidson, PhD; and Philip Gregory, DPhil. I look forward to learning from them and to seeing so many of you next year in Baltimore.
Finally, we wouldn’t have an Annual Meeting without all of your top-tier research! Submit your abstracts through Jan. 26 for the opportunity to present your work during the meeting in front of the largest group of CGT professionals.
I hope you have an enjoyable and restful holiday season and I’ll see you in 2024. Happy New Year!
Sincerely,
Jeffrey S. Chamberlain, PhD
ASGCT President
Breaking Through
TLR9-independent CD8+ T Cell Responses in Hepatic AAV Gene Transfer Through IL-1R1-MyD88 Signaling
Kumar SRP, Biswas M, Cao D, Arisa S, Muñoz-Melero M, Lam AK, Piñeros AR, Kapur R, Kaisho T, Kaufman RJ, Xiao W, Shayakhmetov DM, Terhorst C, de Jong YP, Herzog RW
DOI: https://doi.org/10.1016/j.ymthe.2023.11.029
Summary by Jon Brudvig, PhD
While AAV has shown tremendous utility as a gene therapy vector, immunogenicity continues to be a limiting factor for many indications. Preexisting immunity can preclude effective transduction in seropositive patients, and vector-induced immunity remains a persistent barrier to redosing. High doses of some vectors have triggered severe and sometimes fatal immune-related toxicities. Even in the absence of acute toxicity, immune responses can shut down therapeutic gene expression, neutralize the transgene protein product, or eliminate transduced cells, all culminating in a loss of durable efficacy. Despite these critical consequences, relatively little is known about how these immune cascades develop. In a recent Molecular Therapy article, Sandeep Kumar and colleagues reveal new insights into how these responses are initiated and propagated in the liver.
Paradoxically, transduction of the liver with AAV can induce both immune tolerance and immune activation, with higher doses favoring tolerance. In these studies, Kumar et al. utilized lower doses of an AAV8 vector, which transduced only a minority of liver cells and induced immune responses (transgene and capsid-specific CD8+ T-cells and circulating antibodies) in most animals. Prior studies have suggested that AAV cassette sensing by TLR9 is a key initiator of these responses, but, here, TLR9 knockout mice mounted anti-transgene immune responses that were similar to wild type mice, suggesting that another pathway must be responsible.
Through extensive studies in various strains of genetically immunodeficient mice, the authors found that these liver-mediated immune responses were instead due to activation of Interleukin 1 receptor, type I (1L1R1, a key innate immunity receptor) and the downstream adapter protein Myd88. In the days following delivery, AAV triggered a complex series of interactions between transduced liver cells, plasmacytoid dendritic cells, conventional dendritic cells, Kupfer cells, and infiltrating T-cells. Eventually, this local immune response from these co-clustered cells transitioned to a full-blown systemic response characteristic characterized by circulating antigen-specific T- and B-cells.
Understanding this TLR9-independent response will have important implications for the development of gene therapy immune regimens. Existing efforts to avoid AAV immunogenicity have largely focused strategies to avoid TLR9 activation, such as depleting CpG motifs in the cassette. Even with these mitigation efforts, however, many clinical candidate vectors have had issues with immunogenicity and durability. This new work supports the emerging idea that a multifaceted approach could find much greater success. Avoiding TLR9 activation while also blocking other propagators of innate immunity such as IL1R1 could go far to alleviate early innate responses, leading to reduced toxicity and enhanced durability of expression.
From Molecular Therapy
Read the position description here and submit your CV and cover letter by Jan. 31, 2024.
NEW: Listen to episode 1 of the Molecular Therapy Podcast! In this episode, Dr. Norbert Pardi discusses a recent article published in the September issue of Molecular Therapy that he authored with colleagues, "Development of an mRNA-lipid Nanoparticle Vaccine Against Lyme Disease."
Active Calls for Papers
Biomanufacturing in gene and cell therapy (deadline: Jan. 15, 2024)
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
Final Month: Apply for Congressional Policy Fellowship Through Jan. 15
There's one more month to apply for the ASGCT-AAAS Congressional Policy Fellowship! If you're interested in working directly with legislators on Capitol Hill to influence CGT policy, apply through Jan. 15, 2024. Fellows serve alongside congressional staff, bringing scientific rigor and expertise to the office in which they choose to work. Learn more about this paid position here.
Register Early for #ASGCT24 and Receive the Lowest Rates
Did you know ASGCT members can save $385 by registering early for the 27th Annual Meeting? Lock in the lowest rates and secure your spot during the early-bird period, which ends Feb. 29, 2024. Next year's meeting is expected to be our largest yet, with more than four days of expert-led sessions, abstract presentations, networking opportunities, and so much more. Join us in Baltimore or virtually!
CRISPR Just Made History - Discuss Its Applications Tomorrow, Dec. 15
During our first relaunched Professional Development Café, speaker Julian Grünewald, MD, PhD, and moderator Ben Kleinstiver, PhD, will join us tomorrow at 1 p.m. (CT) to talk about CRISPR! On the heels of last week's first-approved therapy in the U.S. using the gene editing tool, we'll dive into CRISPR's applications in research and medicine. Free for members!
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.
Public Policy
Letter to CBER Highlights CGT Considerations Along Development Spectrum
Earlier this fall, the Center for Biologics Evaluation and Research (CBER) published a request for information (RFI) from stakeholders regarding individualized cellular and gene therapies (CGTs). As the RFI notes, scientific opportunities and challenges are present along the entire development pathway across manufacturing, non-clinical, and clinical spaces. The Society submitted a response highlighting the need for clear guidance on interpreting clinical data, especially in the context of rare diseases and individualized treatments.
ASGCT's letter to FDA underscored critical considerations for advancing the field of CGTs. Key requests included advocating for collaborative platforms to enhance manufacturing consistency; proposing guidelines tailored to the unique risk-benefit profiles of individualized CGTs; and urging flexibility in leveraging nonclinical and clinical data for related products and rare diseases. The letter emphasized the importance of standardization in manufacturing and analytical methods while acknowledging the significance of initiatives like the Advanced Manufacturing Technologies Designation Program. Overall, ASGCT sought regulatory guidance that aligns with the distinctive challenges and opportunities presented by CGTs, promoting innovation and efficiency in their development and approval processes.
Comments to FDA Call for More Regulatory Flexibility for CGTs
ASGCT also appreciated the opportunity to comment on FDA's draft guidance Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products. The Society recently submitted comments to the Agency stressing the importance of clear, accessible, and flexible guidance that accommodates the evolving nature of CGT development.
Feedback centered around concerns regarding the draft guidance's stringent requirements on statistical references for comparability studies, particularly when dealing with limited sample lots. Additionally, comments highlight apprehensions about the lack of adaptability in the draft guidance, which could impede the evolution of CGT products outside conventional regulatory frameworks. ASGCT specifically advocated for:
-
Alternative methodologies tailored to smaller-scale studies and urged regulatory flexibility to foster innovation in manufacturing technologies.
-
Prompt communication from the FDA regarding changes impacting product status, and suggested sponsor options to circumvent proposed manufacturing alterations if they risk clinical hold or a new investigational new drug application (IND).
-
Clarification on the utilization of Type D and INTERACT meetings to discuss comparability, and recommended these forums provide sponsors with a defined timeframe for responses and elucidation on requisite comparability data.
The Society’s comments underscore the inevitability of manufacturing changes in CGT product development. With that in mind, ASGCT will continue to advocate to FDA for a comprehensive approach to product regulation that enhances efficiency while protecting patient safety.
FDA, NIH Funding Remains Uncertain Ahead of 2024
Late last month, President Biden signed into law a bipartisan, two-tiered Continuing Resolution (CR) to avoid a government shutdown ahead of the previous funding deadline. This new CR (H.R. 6363) extends the deadlines for fiscal year 2024 (FY24) appropriations packages into early 2024. ASGCT appreciates both chambers working to avoid a shutdown, as funding lapses would negatively impact federally funded research and development.
With a CR in place, both chambers may resume work on their appropriations packages. The appropriations bill that funds FDA will be due January 19, and the bill funding NIH will have a deadline of February 2. Both chambers will need to work to reconcile their respective versions of each bill before sending on to President Biden for signature.
First Gene Therapies for Sickle Cell Disease Approved in U.S.
On Friday, Dec. 8, FDA approved two gene therapies to treat sickle cell disease (SCD) in patients 12 or older: Casgevy (exagamglogene autotemcel, or exa-cel) and Lyfgenia (lovotibeglogene autotemcel, or lovo-cel).
These therapies represent the first gene therapies approved for SCD in the U.S., and, notably, Casgevy is the first CRISPR-based therapy to receive FDA approval. Developed by CRISPR Therapeutics and Vertex, Casgevy utilizes CRISPR-Cas9 gene editing to modify a patient's own hematopoietic stem cells (HSCs) ex vivo. The edited cells are then reintroduced into the patient's body, producing elevated levels of fetal hemoglobin and enabling the generation of healthy red blood cells. Lyfgenia, developed by Bluebird Bio, employs a lentiviral vector for genetic modification. Lyfgenia works by adding a functional β-globin gene to patients’ own HSCs. ASGCT’s Board President recently shared more detail on the exciting science behind these innovative therapies.
The development of gene therapies for SCD will be transformational for patients grappling with this debilitating condition. For individuals affected by SCD, gene therapy opens a new chapter of hope, promising transformative outcomes and improved quality of life for individuals long awaiting effective and durable solutions.
Apply to Serve on ASGCT Standing and Scientific Committees
ASGCT strives to advance knowledge, awareness, and education leading to the discovery and clinical application of genetic and cellular therapies to alleviate human disease. Our mission is fulfilled by member-directed projects led by our 33 standing and scientific committees. Within the Society, our committee members serve as subject matter experts on topics spanning hematology, immune response, global outreach, ethics, government relations, and more.
Applications are open for the 2024 committee cycle for anyone interested in getting more involved with ASGCT. Mark your calendars; this year’s applications are due January 17! Committee appointees must be ASGCT members and submit a short excerpt on their relevant experience. More information on the appointment process and committee expectations can be found here.
Industry News
View the Rate Sheet