The Vector

Volume 10, Issue 1: January 2021


Editorial Team

Edith Pfister, Ph.D. – Editor, The Vector
Karen Bulaklak, Ph.D. – Associate Editor, The Vector
Jon Brudvig, Ph.D. – Junior Editor, The Vector

Inside This Issue

Leadership Message
Breaking Through
Society News
Career Center
Public Policy
Industry News

Leadership Message


Encourage Vaccine Participation by Sharing Our New Resources

Happy New Year, ASGCT Members!

I hope you’re coming into 2021 refreshed and excited to submit your abstracts for the upcoming Annual Meeting. We have a lot of exciting initiatives coming this year that I can’t wait to share them with all of you.

If you haven’t already, please take some time to check out our new Patient Education resources about the mRNA vaccines for COVID-19. The resources include a video, infographic, and answers to some of the most frequently asked questions about the vaccines.

As scientists, I believe it’s our duty to show the public that these vaccines are safe and effective in order to strengthen their trust in the scientific community. In that spirit, please share these resources with your colleagues, family, and friends so that we can encourage vaccine participation. Thank you to the committee volunteers and ASGCT staff members that developed these resources quickly and distributed them over the holiday break.

As we’re getting closer to the 24th Annual Meeting, please remember to submit your abstracts! Submitting an abstract gives you the opportunity to present and discuss your research with thousands of professionals during what has become the leading event for gene and cell therapy. You can also earn awards for high-scoring research and you’ll be published for free in a special Molecular Therapy supplement. If you’re an Associate Member and a first and presenting abstract author, you can register for the meeting for free.

Lastly, I want to mention that we have developed a new digital presentation experience for the abstracts that are traditionally presented as posters at the Annual Meeting. This new format goes beyond the constraints of a traditional poster and will allow you to record and upload your own narrated presentation, use built-in live chat and direct messaging tools to engage with viewers, and more. We are confident this will create more meaningful interaction between attendees and we look forward to hosting your abstract at the meeting!

Stay safe!
 

Sincerely,

Stephen J. Russell, M.D., Ph.D.
ASGCT President 

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Breaking Through


Enhanced Efficacy and Increased Long-Term Toxicity of CNS-Directed, AAV-Based Combination Therapy for Krabbe Disease

Li Y., Miller CA, Shea LK, Jiang X, Guzman MA, Chandler RJ, Ramakrishnan SM, Smith SN, Venditti CP, Vogler CA, Ory DS, Ley TJ, and Sands MS ​

DOI: https://doi.org/10.1016/j.ymthe.2020.12.031

Summary by Jon Brudvig, Ph.D.

Hepatocellular carcinoma (HCC) has been a recurring, controversial concern in the AAV gene therapy space. Wild-type AAV sequences have been detected in human HCC tumors, and liver integration of AAV gene therapy vector has been observed in animal models, driving concerns over potential genotoxicity. However, causal relationships between AAV gene therapy and HCC have not been firmly established, and with the exception of a single recently disclosed case, new post-treatment liver tumors have not been observed in gene therapy patients. These concerns are likely to be reignited following a recent Molecular Therapy publication from Li et al (2020), in which the authors document nearly complete penetrance of HCC in mice treated with a combination of AAV gene therapy, hematopoietic stem cell transplantation (HSCT), and small molecule substrate reduction therapy.

In this study, the authors build upon an earlier combinatorial strategy for treating Krabbe disease, a lysosomal storage disorder caused by a deficiency in galactosylceramidase (GALC). The first-generation therapy utilized CNS-directed high-dose AAV5-GALC gene therapy and HSCT for restoration of enzyme activity, combined with chronic L-cycloserine treatment for substrate (psychosine) reduction. The therapy synergistically reduced substrate accumulation and increased lifespan but did not prevent late‑stage pathology or behavioral abnormalities. In the present study, the authors sought to improve biodistribution, transduction, and subsequent efficacy by switching the gene therapy component to a more efficient AAV9 capsid.  

This second-generation combination strategy resulted in longer lasting behavioral improvement and further increases in lifespan but introduced a surprising safety concern; most of the treated animals (33/35) succumbed to advanced HCC. Development of HCC seemed to be a result of a toxic synergy between the three components of the therapy; mice treated only with gene therapy and HSCT had a far lower incidence of HCC (2/14), and mice treated solely with any one component did not develop tumors. Importantly, every tumor that was examined had AAV integrations, with many near tumor suppressor genes and within the oncogenic, mouse-specific Rian locus. While the precise etiology of these tumors was not determined, the authors hypothesize that L-cycloserine stimulated tumor growth following AAV integrations in hepatocytes, cells which AAV9 transduces with extremely high efficiency.

It has been established in preclinical models that hepatic AAV integrations can occur following gene therapy treatment, but whether these integrations present risks or even benefits (from increased expression) has been the subject of intense debate. It is unclear how relevant HCC results in mice are to human patients, and the extremely low incidence of tumors in clinical trial populations remains very encouraging. Still, these important and unexpected results from Li, et al. highlight the potential for unanticipated interactions between AAV gene therapy and other therapeutic regimens, environmental influences, or disease conditions.

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Society News


Share Our New mRNA Vaccine Resources

ASGCT has developed new educational resources to explain how the recently authorized mRNA vaccines work and why they are safe and effective against COVID-19. Now available on our Patient Education site, these resources include a short video, infographic, and answers to frequently asked questions about the vaccines. Please share these resources with your colleagues, family, and friends so we can inform, ease fear, and celebrate this accomplishment in the gene therapy field!

Submit Your Abstracts by Jan. 27

Submitting an abstract is a great way to present and discuss your gene and cell therapy research with leaders in the field during the 24th Annual Meeting. If you're an Associate Member and the first and presenting author, you can register for the meeting for free! Select topic categories that describe your work and submit today!

Renew Your Membership to Save at the Annual Meeting

ASGCT Members receive the lowest rates on registration for the Annual Meeting, so make sure you renew your membership to receive the registration discount and other exclusive benefits. New this year: The first 1,000 Annual Meeting registrants with a valid U.S. mailing address will receive a VIP Pack, presented by Sarepta Therapeutics, filled with stay-at-home necessities for the meeting.

Volunteer for an ASGCT Committee

We're now accepting nominations from ASGCT Members who are interested in serving on committees or recommending colleagues to do so. To self-nominate or submit a recommendation, please complete this form.

Funding Opportunity: Submit Research on Gene Therapy for NF1 

The Gilbert Family Foundation's (GFF) Gene Therapy Initiative announced a Request for Proposal for high-impact research on gene therapy strategies aimed at addressing the loss of neurofibromin 1 (NF1) gene function in neurofibromatosis type 1 patients. Visit GFF's website for more information on the application process.

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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

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Public Policy


CMS Enables Outcomes-Based Payment Methods for Innovative Therapies

Last month, the Centers for Medicare & Medicaid Services (CMS) issued a final rule that in 2022 will provide states, private payers, and manufacturers with more flexibility to enter into value-based purchasing (VBP) arrangements for innovative therapies by allowing reporting of multiple Medicaid best prices. ASGCT has advocated since 2018 for this removal of barriers to VBP models for gene therapies. Payment amounts under such agreements are partially driven by their value to individual patients, thereby distributing risk between payers and manufacturers. Anticipated savings to the Medicaid program promotes program sustainability, and therefore patient access to treatment.   

Under the Medicaid Drug Rebate Program (MDRP), manufacturers must provide rebates to state Medicaid programs of a baseline amount or more in order to provide their “best price” to CMS for brand name drugs and biologics. Rebate rules and related reporting requirements have not been updated in 30 years. 

“Medicaid’s outdated rules have consistently stymied the ability of payers and manufacturers to negotiate drug reimbursement methods based on the actual outcome of the treatment,” said CMS Administrator Seema Verma. “A new generation of approaches to payment methods is needed to allow the market the room to adapt to these types of curative treatments while ensuring that public programs like Medicaid remain sustainable and continue to receive their statutorily required discounts.” 

ASGCT-Supported Federal Funding Increases Pass 

As a result of advocacy from ASGCT and many other organizations who helped to highlight the value of robust federal funding, the final 2021 omnibus budget bill, signed into law December 27, included FY 2021 increases of $1 billion for NIH and $42 million for FDA. Dedicated funding for the SCD Data Collection Program was also included in the omnibus bill. Earlier in December ASGCT added its voice to two collaborative efforts to support federal research funding. The first requested inclusion of dedicated funding in the fiscal year (FY) 2021 appropriations bill for the Centers for Disease Control and Prevention’s (CDC) Sickle Cell Disease (SCD) Data Collection Program. The second letter supported an increase in FY 2021 appropriations for the National Institutes of Health (NIH) and Food and Drug Administration (FDA).

Industry News


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2021

ASGCT 24th Annual Meeting

May 11-14, 2021