The Vector
Editorial Team
Karen Bulaklak, PhD – Editor, The Vector
Jon Brudvig, PhD – Associate Editor, The Vector
Inside This Issue
Leadership Message
Breaking Through
From Molecular Therapy
Society News
Career Center
Public Policy
Industry News
Leadership Message
Insight Series Returns Next Month
Hello, ASGCT Members,
I’m excited to let you know that ASGCT’s Insight Series will be back next month! If you’re new to ASGCT or haven’t attended one of these sessions before, they’re an excellent (and free for Members) way for you to take an in-depth look at new research into a variety of topics in the field. On October 5, join us for Novel CAR-T Cell Therapies for Malignancies. During this session, our expert speakers, Cliona Rooney, PhD, Julia Carnevale, MD, and Beau Webber, PhD, will discuss the challenges of including off-the-shelf treatment options for solid tumors. They will also update attendees on how CRISPR-based genome editing technologies are being applied to help us better understand T-cell function and how to create novel T-cell products for patients. I encourage you to check out our past on-demand Insight Series sessions and register to join us in October! Check back to the website later this month, as we’re holding another session Oct. 19 about delivering gene therapy to skeletal muscles. All sessions are available to watch on demand for Members and registrants.
Luckily, we have plenty of other opportunities this month if you can’t wait until October. In just two weeks, we’re hosting a symposium with the International Society for Stem Cell Research (ISSCR) in Madison, WI, and virtually. Symposium speakers, including many of our own Members, like Donald Kohn, MD, and Michel Sadelain, MD, PhD, will highlight their groundbreaking work developing therapies for diseases and discuss application of gene-editing technology. All Members can register for this symposium at a reduced rate; learn how to do that here.
And finally, Sept. 26-27, we’re heading back to Washington, D.C. for our fourth annual Policy Summit. While there is limited seating for the in-person portion, we still have spots open, so don’t wait to register! You’ll hear about some of the key issues in gene therapy, like PDUFA reauthorization, accelerated approval, and how the Biden administration’s priorities for Medicaid could affect the field.
Take care and be well,
Hans-Peter Kiem, MD, PhD
ASGCT President
Breaking Through
IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice
Butterfield JSS, Yamada K, Bertolini TB, Syed F, Kumar SRP, Li X, Arisa S, Piñeros AR, Tapia A, Rogers CA, Li N, Rana J, Biswas M, Terhorst C, Kaufman RJ, de Jong YP, Herzog RW
DOI: https://doi.org/10.1016/j.ymthe.2022.07.005
Summary by Jon Brudvig, PhD
As AAV-mediated gene therapy has matured, the field has made great strides in understanding critical safety issues and factors impacting short-term efficacy. Achieving long-term durability, however, remains challenging for some indications, due largely to the paucity of animal models that can recapitulate the slowly declining expression observed in some clinical trials. In a recent Molecular Therapy article, Butterfield and colleagues present a new mouse model that mimics the protracted decline in expression observed in AAV clinical trials for hemophilia A, and they use this model to dissect key factors impacting durability.
Some indications, like hemophilia B (caused by a deficiency in factor IX), have been treated with great success with liver-directed gene replacement. Hepatocytes are the endogenous source of factor IX and seem to tolerate long-term overexpression of factor IX transgenes, with clinical demonstration of durable expression for at least eight years. Gene replacement with factor VIII for hemophilia A, however, has been more challenging. Factor VIII is naturally produced by endothelial cells, and it has long been hypothesized that the ectopic expression driven by hepatocyte-directed AAVs may induce cellular stress that hinders durability. Precisely how that cellular stress results in declining expression has been the subject of debate.
In this study, Butterfield et al. show that hemophilia A mice on the BALB/c background can be utilized as a model for declining durability. When treated with an AAV8 vector expressing human factor VIII along with eight weeks of rapamycin for short-term immunosuppression, these mice exhibit a protracted decline in factor VIII expression without antibody responses, just as in human clinical trials. Surprisingly, in these mouse studies, factor VIII activity declines were not accompanied by similar declines in transcript levels, pointing to translational shutdown as a primary issue driving the lack of durability. Further experiments suggest that this translational shutdown is driven by a complex milieu of cellular stress, noncytotoxic responses from CD8+ T-cells, and responses from innate immune cell populations. The authors go on to show that blockade of IL-15 signaling can interrupt these processes and alleviate translational shutdown, prolonging expression.
It remains to be seen whether these results hold in other tissues, organisms, and indications. Durability is influenced by a broad set of factors involving cellular stress, AAV genome stability, and innate and adaptive immune responses. Still, this work adds an important new wrinkle to our understanding of AAV gene therapy durability and could one day contribute to new adjunctive therapies that enable the ultimate goal of life-long expression.
From Molecular Therapy
Molecular Therapy impact factor reaches 12.9 in 2021
The impact factor of our flagship journal Molecular Therapy inreased to 12.9 in 2021–the highest value in its history! The increase represented a 12.6 percent jump for the journal from 2020 to 2021. Read Dr. Herzog's blog post.
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
New Free Course: Introduction to Gene Therapy for Educators
Registration is now open for a free eight-part course that will equip faculty with the knowledge and skills to educate students on advances in clinical gene therapy. If you're teaching at an accredited university or medical school in sub-Saharan Africa or another low-resource setting, learn more about this opportunity on our website. Register by Sept. 16.
Save on Registration for ASGCT-ISSCR Symposium
As an ASGCT Member, you can save at least $400 when you register for our joint international symposium with ISSCR Sept. 21-23. Learn about the latest advancements in regenerative medicine from international experts, including many of our own Members! Register now and we hope to see you there.
Oct. 17-18: NORD Summit is Back in Washington, D.C.
Register now for the National Organization for Rare Disorders (NORD) Rare Disease and Orphan Products Breakthrough Summit, which returns in person to Washington, D.C. Oct. 17-18. This event brings together rare disease experts, patient advocates, and more to provide their insights on rare disease topics. Learn more on NORD's website.
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.
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Featured Jobs
Public Policy
Some States Implement Restrictive Medicaid Coverage of GCTs, Survey Finds
In an effort to help elucidate the issues surrounding Medicaid coverage of gene and cell therapies, ASGCT’s Government Relations Committee recently published an editorial on survey results. In their findings, the authors compared a selection of state Medicaid and Medicaid managed care organization (MCO) coverage policies for three FDA-approved advanced therapies – Luxturna, Kymriah, and Zolgensma. The results of this survey, along with anecdotal evidence from patients and providers, confirm that some states are implementing restrictive Medicaid coverage of cell and gene therapies, often limiting access to populations defined by the eligibility criteria for the clinical trial(s) rather than the FDA-approved labeled indication.
ASGCT supports modernizing coverage and payment policies to foster patient access to the FDA-approved indication of gene and cell therapies. Innovative payment models should account for the unique characteristics of the therapy and the disease it is intending to treat. As the pipeline for cell and gene therapies continues to grow, ASGCT encourages federal and state regulators to take proactive steps to ensure that payment systems are ready and designed for this type of innovation so that patients can readily access these therapies.
Gene Therapy for Beta Thalassemia Approved in the U.S.
On August 17, FDA approved betibeglogene autotemcel (beti-cel), a gene therapy to treat the underlying cause of beta thalassemia in adult and pediatric patients. The approval of beti-cel, marketed as Zynteglo, marks several milestones in the United States: it is the first lentiviral vector-based gene therapy granted FDA approval; the first gene therapy approved for patients with a chronic disease; and only the third gene therapy approved for any inherited genetic disease.
FDA held an advisory committee meeting earlier this year to seek an outside assessment of the risk/benefit profile of two gene therapies from bluebird bio, including beti-cel. The advisory committee recommended that the benefits outweigh the risks of treatment for both the recently approved therapy and eli-cel, intended for certain patients with cerebral adrenoleukodystrophy (CALD). Eli-cel has an upcoming PDUFA date of September 16.
The approval of beti-cel represents a huge step forward for beta thalassemia patients, giving them the option to pursue a one-and-done treatment approach. Following the announcement, ASGCT's President shared more detail about the science behind beti-cel and how it can help treat blood disorders.