The Vector
Volume 10, Issue 10: October 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
From Molecular Therapy
Society News
Career Center
Public Policy
Industry News
Leadership Message
Renew Your Membership for Uninterrupted Benefits Through 2022
Hello ASGCT Members,
It’s hard to believe we’re already into the fall, but you know what that means—it’s time to renew your ASGCT membership. By renewing right now, you’ll maintain all the exclusive benefits of membership through 2022 with no interruption. That means you can continue to connect with your peers through your service on committees, keep learning about the latest advances in the field with your Molecular Therapy subscription, and enjoy on-demand access to all of our Professional Development Cafés, among other benefits. With all of the challenges we’ve experienced in the last year and a half, it’s comforting to know that ASGCT can remain our professional “home base” and we can all utilize the connections we make and the knowledge we gain as members to keep moving the field forward. Thank you for being a member of ASGCT, and I hope you’ll join me in renewing your membership in the largest, most inclusive gene and cell therapy community.
While you’re renewing your membership, please make sure your member profile is up to date. If you’ve switched jobs or changed your email address, add any new information to your profile so that you continue to receive updates about what’s happening at ASGCT.
Speaking of ASGCT’s upcoming events, we have an excellent Professional Development Café next Friday, Oct. 22, “How To” with Cas 9 and CRISPR. During this free virtual event, we’ll hear from Ben Kleinstiver, PhD, whose lab seeks to address limitations of CRISPR genome editing technologies. Dr. Kleinstiver is interested in answering important research questions at the forefront of the genome editing field, so bring any and all CRISPR questions you have for him.
Last but not least, there’s still time to register for the hybrid International Oncolytic Virus Conference (IOVC) Nov. 5-7. We’re looking forward to being back in person in Sedona, AZ, for this event, but in-person attendance is limited. If you’re thinking about attending in person, you can read about the health and safety protocols that ASGCT has implemented on our website. In-person registration is open through Oct. 28.
Sincerely,
Beverly L. Davidson, PhD
ASGCT President
Breaking Through
A Comprehensive Study of a 29-Capsid AAV Library in a Non-Human Primate Central Nervous System
Kondratov O, Kondratova L, Mandel RJ, Coleman K, Savage MA, Gray-Edwards HL, Ness TJ, Rodriguez-Lebron E, Bell RD, Rabinowitz J, Gamlin PD, Zolotukhin S
DOI: https://doi.org/10.1016/j.ymthe.2021.07.010
Summary by Jon Brudvig, PhD
Limited target-cell transduction is a persistent hurdle for AAV gene therapies in the CNS. Given the dose limits imposed by toxicity and manufacturing constraints, therapy developers seek potent capsids that deliver active transgenes to as many target cells as possible. Likewise, delivery methods are continually being optimized in an effort to maximize on-target delivery. Finding the ideal combination for a given disease has been no easy task, especially given the lack of published quantitative, head-to-head comparisons of transduction efficiency for the multitude of available capsid / route of administration combinations. Here, Kondratov et al. present a comprehensive investigation into patterns of transduction and expression with 29 different capsids, each delivered with four commonly used routes of administration.
With 29 capsids, four routes of administration, six nonhuman primate (Macaca fascicularis) subjects, and quantification of DNA and RNA within 15 distinct CNS areas, the study required analyses for a staggering 6,128 data points. The authors addressed this with a novel DNA barcoding strategy in which each combination was assigned a unique set of barcode sequences within the vector and within the primers used for amplification. This allowed for precise, quantitative assessment of biodistribution and expression using next generation sequencing. Intraparenchymal (putamen, IP), intracerebroventricular (ICV), intra-cisterna magna (ICM), and lumbar intrathecal (IT) routes were utilized. Transduction and expression were assessed in discrete areas throughout the forebrain, midbrain, and hindbrain.
There were striking differences in efficiency for the various capsid/route combinations. Several capsids stood out for their high production of transcript following IP delivery, with AAV2-2i8, AAV7, AAV9‑PHP.B, AAV-rh10, AAV1D265, and AAV1 performing best in most brain areas. There was a clear front runner for the three CSF delivery methods, with AAV-DJ yielding the highest expression across most areas. AAV-rh10, AAV9-PHP.B, AAV7, AAV8, and AAV-B1 also performed well across the CSF delivery routes. Some capsids (AAV5, in particular) yielded high levels of transduction at the DNA level that did not translate to high transcript levels, demonstrating the dramatic effect that capsid composition can have on post-uptake trafficking and processing.
Using a combined analysis for all capsid/route combinations along with time-lapse fluoroscopy, the authors also investigated patterns of AAV exposure across different brain regions. Interestingly, AAV spread was shown to occur independent of CSF flow, with high transduction both upstream and downstream relative to CSF flow. Given the ongoing debate around superiority of ICM versus LP or ICV delivery methods, the authors also compared overall transduction patterns for the three routes, finding little difference and noting that “the choice of the injection route for a multifocal CNS delivery, in a clinical setting, should be governed by practical considerations of the surgery, rather than the notion of higher vector penetrance.”
With the multitude of newly developed capsids and explorations into new routes of administration, this work is an important step forward for CNS gene therapy. While further differences will surely emerge with alternative transgenes, vector elements, and doses, therapy developers can use the data presented here as a starting point for rational selection of promising capsids and delivery strategies.
From Molecular Therapy
Molecular Therapy—Methods and Clinical Development call for papers: Submit a paper to a special issue on evidence generation and reproducibility in cell and gene therapy research. Learn more about this special issue by reading this editorial and submit a paper by February 28, 2022.
Check out the latest issue of Molecular Therapy here, and don't miss the most recent content from other issues in the MT family:
Society News
Maintain Your Membership Benefits by Renewing Today
It's renewal season at ASGCT! If you renew your membership right now, you'll lock in the same exclusive benefits you enjoy as a member all the way through 2022. Continue to receive discounts for events and for publishing your work in Molecular Therapy, maintain eligibility for awards, and more. While you're renewing, make sure your contact information in your member profile is current so that we can stay in touch with you.
Watch ASGCT's Indo-UK Symposium On Demand
ASGCT held a free virtual symposium for researchers in India on October 9, and the full event is available on demand on ASGCT’s YouTube channel. Speakers addressed the challenges of developing gene therapies in a lower-middle income country as well as potential solutions. Created by the Global Outreach Committee, the goal of the event was to increase access to gene and cell therapies in countries with low- and middle-income economies.
Join the Rare Disease Community at Next Week's NORD Summit
Register now for the National Organization for Rare Disorders (NORD) Rare Disease and Orphan Products Breakthrough Summit Oct. 18-19. This virtual event brings together rare disease experts, patient advocates, leaders at FDA and CDC, academia, and industry to discuss critical topics in the rare disease and orphan products field. More information is available on the Summit's website.
Register for Upcoming ASGCT Events
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
FDA Approves First CAR T-Cell Therapy for ALL
Earlier this month, the Food and Drug Administration (FDA) approved brexucabtagene autoleucel (Tecartus) for a new indication—adult patients (18 years and older) with relapsed or refractory (r/r) B-cell precursor acute lymphoblastic leukemia (ALL). This approval makes Tecartus the first CAR T-cell therapy for ALL for adults. Tecartus received accelerated approval for another indication, adults with r/r mantle cell lymphoma, in July 2020.
“There is a large population of adult patients with ALL who had relapsed or refractory ALL who did not have an option outside a clinical trial and now have access to an approved CAR-T therapy,” said ASGCT Past President Helen E. Heslop, MD, DSc. (Hon).
This CD19-directed CAR T-cell therapy resulted in a 52 percent complete response within three months in a single-arm multicenter trial in the new treatment population, with median duration not reached at 7.1 months median follow-up. The FDA granted the approval to Kite Pharma, Inc., a Gilead Company, which received priority review, breakthrough designation, and orphan drug designation for this application.
Tecartus is one of eight gene therapies approved in the U.S., as defined in ASGCT’s series of quarterly landscape reports, and is one of five approved CAR T-cell therapies. Novartis’ tisagenlecleucel (Kymriah) treats a slightly overlapping population of pediatric and young adult patients (age 3-25 years) with B-cell precursor ALL that is refractory or in second or later relapse.
Policy Summit Tackles Regulatory, Legislative, and Access Issues
At ASGCT’s third annual Policy Summit last month, presenters shared their expertise on key regulatory and legislative policy issues in the gene and cell therapy field. Highlights of the event, held in person and virtually, included discussions on the challenges and options for solutions in Medicare and Medicaid payment policy for gene therapies, which affects patient access to these therapies. For example, Diane Berry, PhD, senior vice president of global health policy, government and patient affairs at Sarepta Therapeutics, advocated for state Medicaid programs to cover gene therapies for all FDA-labeled populations, rather than restricting coverage to patients who meet clinical trial eligibility criteria.
The Policy Summit also tackled key regulatory and payment policy issues surrounding FDA’s accelerated approval program , such as payer misconceptions about the regulatory pathway. Speakers offered strategies to address these challenges, including reconsideration of labeling to indicate FDA found benefit to outweigh risk, and improvements in post-market confirmatory trial processes and requirements.
In addition, the event covered significant issues in the field that have potential policy and advocacy implications, such as workforce development challenges and the need for the continual centering of patients in gene therapy development. A session on AAV vector integration included a summary from ASGCT’s AAV Integration Roundtable on the status of research and gaps in knowledge about this phenomenon and its clinical implications.
Catch more sessions on diagnostic testing and proposed FDA user fee commitments, along with all of this year’s Policy Summit content, on demand on the meeting platform through October 24. Not registered? You can still register and get full access to the presentations!
Industry News
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