Volume 9, Issue 12: December 2020


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


Register Now for the Virtual 24th Annual Meeting

Hello ASGCT Members,

As I look back on what has been a difficult year for everyone, I want to first let you know how proud I am of all the work that our Society has done. We quickly pivoted to a virtual platform for the 23rd Annual Meeting—an event that broke attendance and abstract submission records. We brought together virus experts who not only helped us understand COVID-19, but showed us how they were working to fight it. We launched a new Patient Education website and resources. We held our second annual Policy Summit. Just last week, we held our first collaborative meeting with the Brazilian Association of Cellular and Gene Therapy. Please join me in celebrating all of these accomplishments because we couldn’t have done any of them without your support!

While we’re on the subject of membership, I encourage you to renew before Dec. 31 if you haven’t already! As a Member, you’ll be among the first to learn about the innovative programming that we have planned for 2021. Don’t lose access to your benefits; make sure you renew today.

One of those exclusive membership benefits is a registration discount for the 24th Annual Meeting! We announced earlier this week that registration is now open for the virtual meeting May 11-14, 2021. We can’t wait to show you the new platform, which has expanded features for learning and networking in addition to the cutting-edge scientific and educational programming you’re used to every year. The first 1,000 registrants with valid U.S. addresses will receive a VIP Pack, presented by Sarepta Therapeutics, filled with stay-at-home necessities for the meeting.

Finally, I hope you’re able to take some time to relax and enjoy a (socially distant) holiday season. Thank you for your membership, and Happy New Year!

Sincerely,

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

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Breaking Through


Methods Matter: Standard Production Platforms for Recombinant AAV Produce Chemically and Functionally Distinct Vectors

Rumachik NG, Malaker SA, Poweleit N, Maynard LH, Adams CM, Leib RD, Cirolia G, Thomas D, Stamnes S, Holt K, Sinn P, May AP, Paulk NK

DOI: https://doi.org/10.1016/j.omtm.2020.05.018

Summary by Edith Pfister, Ph.D.

In preclinical studies, recombinant AAVs (rAAVs) are often produced using transient transfection of human HEK293 cells. However, as development of rAAVs for gene therapy accelerates, there is a desire to improve manufacturing and production technologies to improve yield, reproducibility, and purity. rAAVs can also be produced by infection of Spodoptera frugiperda (Sf9) insect cells with baculovirus. This method is more efficient and produces higher yields than the traditional method and is sometimes thought to be more suitable to clinical production. One important question for translation therefore is whether these two methods produce identical or equivalent rAAV vectors. A paper by Rumachik and colleague seeks to answer this question. The group rigorously compared rAAV vectors made in human HEK293 cells with those made in Sf9 cells. They found that vectors produced in human and insect cells are both extensively modified, particularly on the outside of the capsid. While some modifications are shared between methods, there are also numerous differences in modification between the two methods.

Production in HEK293 cells resulted in more full capsids than Sf9 cells and fewer truncated capsid proteins. Impurities were present in both types of vector prep, but differed depending on the method, which raises the possibility that the Sf9 prep could contain allergenic insect-derived impurities. In addition to post translational modifications, there were small but significant differences in methylation of vector genomes, which could potentially impact vector potency. Finally, the authors tested the potency of vectors produced by different vectors in vivo. Vectors produced in human cells were significantly more potent in a variety of cell types and tissues in vivo.

These findings clearly show that vectors produced by different manufacturing methods differ in potentially important ways and suggest that care should be taken when switching from one method to another. Vectors produced in insect cells may have insect-specific modifications which are potentially allergenic in humans. In addition, although vector yield is higher using baculovirus, those vectors also exhibit lower potency than those produced in HEK293 cells. In my lab’s group meetings, we often discuss the potential for different methods to produce different results but up until now our discussions have been mostly speculative and based on anecdotal evidence. This careful study confirms that indeed, methods matter, and provides some explanation for differences we and others have observed.

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Society News


Register Now for #ASGCT21 and Receive a VIP Pack

Registration is now open for the 24th Annual Meeting, which will be held on a brand new virtual platform May 11-14, 2021! Register before May 1 to receive the lowest rate. If you're part of a group of five or more registrants from the same institution, you'll receive a 10% discount. The first 1,000 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.

Last Chance: Renew Your Membership for 2021

Please remember to renew your membership for 2021 by December 31! As an ASGCT Member, you'll receive the lowest rates on registration for events like the Annual Meeting, maintain access to research in Molecular Therapy, and be the first to know about the programming we have planned for 2021. Renew today!

Submit Your Abstracts by January 27

We want to see your research! Submit an abstract and you may be able to present during the 24th Annual Meeting. You may also be eligible for an award for your work. Visit this section of the Annual Meeting website for submission and presentation information, select topic categories that describe your work, and submit by January 27, 2021. Associate Members: If you're a first and presenting abstract author, you'll receive free registration!

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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


ASGCT and Brazilian Association Hold Joint Meeting

ASGCT held its first ever collaborative event with the Brazilian Association of Cellular and Gene Therapy (ABTCel-Gen) virtually December 2. The ASGCT Global Outreach Committee initiated this program as part of the Society’s strategic goal to foster equitable access to gene and cell therapies in low- and middle-income countries. The program focused on the scientific, infrastructural, and regulatory factors necessary to address when initiating clinical research for gene therapies. More information, including the recording of the program, is available here.

Society Supports Robust Federal Funding

ASGCT recently added its voice to two collaborative efforts to support federal research funding. The first letter requested inclusion of dedicated funding in the final appropriations bill for fiscal year (FY) 2021 for the Centers for Disease Control and Prevention’s (CDC) Sickle Cell Disease (SCD) Data Collection Program. The CDC SCD Data Collection Program assists states in collecting and analyzing data on the prevalence of SCD and health outcomes, complications, and treatment that people with SCD experience. Such data is important for patient access to innovative gene therapy trials for SCD. The letter, sent last month, was spearheaded by the Sickle Cell Disease Coalition.

The second letter, sent this month to the majority leaders of the House and Senate, supported an increase in FY2021 appropriations of at least $2 billion for the National Institutes of Health and $250 million for the Food and Drug Administration. Additionally, the letter supported an emergency COVID-19 spending package that includes at least $26 billion to support the many critical scientific research projects that have been negatively impacted by the pandemic. This letter was led by Research!America.

FDA Staff Offers Insights at ASGCT’s Third Annual Liaison Meeting 

ASGCT held its third annual liaison meeting last month with staff from the Office of Tissues and Advanced Therapies (OTAT) within FDA’s Center for Biologics Evaluation and Research (CBER). Three ASGCT members presented recommendations for immunogenicity testing, preclinical risk assessment, and the use of innovative clinical trial designs to accommodate small patient populations. Additionally, OTAT Director Wilson Bryan, M.D., provided information on a variety of regulatory challenges to gene therapy development.

A common theme during the meeting was the need to balance flexibility and consistency in regulatory decision making. For example, OTAT staff indicated they try to apply a flexible testing strategy, so they consider pharmacology and toxicology requirements on a case-by-case basis using a weight-of-evidence approach. They encouraged sponsors to propose pharm/tox testing with data and rationale to support the proposal. Mercedes Serabian, MS, DABT, Chief of the Pharmacology/Toxicology Branch-1 at OTAT noted that an International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) working group is developing a guideline on biodistribution in gene therapy trials. Similarly, Bryan said that OTAT tries to be consistent across applications, while ensuring they are regulating appropriately for the science behind a particular case.

On the issue of randomization in trials, Bryan stated that OTAT does not insist, but strongly recommends randomization (such as to two dose levels) for first-in-human trials. When asked to comment on the appropriateness of randomization in gene therapy trials in very rare indications where time is of the essence, Bryan replied the question presumes the product is safe and effective, and FDA does not begin with that presumption. He emphasized that for small patient populations, it is even more important to randomize in Phase I to obtain as much evidence as possible from each patient. 

Other insights from the Agency included that, when asked whether six months is becoming a more common requirement for the total duration of toxicology studies, Bryan indicated that FDA would be interested in hearing about cases requiring six months of testing. Another topic FDA staff stressed is the need to have the manufacturing process in place early, including qualification of test methods for CQAs.

ASGCT organizes the liaison meeting annually for its members in clinical development to provide recommendations for FDA consideration and for the Agency to present on a topic of shared interest. This year’s meeting was co-chaired by ASGCT Regulatory Affairs Committee Chair Adora Ndu, PharmD, J.D., Vice President of Regulatory Affairs and Global Head of Policy, Research, Engagement & International at BioMarin Pharmaceutical, and Robert Pietrusko, PharmD, Chief Regulatory & Quality Officer at Vor Biopharma.

A summary of the of the meeting presentations is available here, and slides from the meeting are here.

Industry News


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