The Vector

Volume 10, Issue 4: April 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


Success Strategies for a Virtual Meeting FREE on April 16

Hello ASGCT Members,

A new season is upon us and we have a lot of initiatives to remind you about here at ASGCT! I’m really looking forward to our upcoming programming, both the new and usual events, and I hope you’ll take advantage of everything that your membership offers.

Coming up first is the inaugural event in our Career Development Seminar series, Success Strategies for a Virtual Meeting, which will be held next Friday, April 16. As an ASGCT member, the event is free live and on demand, so register now! These monthly professional development seminars are designed for early-career professionals in gene and cell therapy, but will be helpful for anyone in a scientific field looking to enhance their skills.

For those of you who are Members, Transitional Members, and Emeritus Members, please vote in the 2021 ASGCT election. We’ll be welcoming four new members to the Board of Directors starting June 1, so please help us select those incoming leaders who will guide the Society’s path forward. Learn more about our impressive candidates and vote by April 20.

In order to vote, however, your ASGCT membership must be current, so before you do anything else, renew your membership! We know this past year has been challenging for so many of you, but we want you to keep receiving your benefits so that we can keep moving this field forward together. We’re optimistic for the coming year, the end of the pandemic, and the future of our field, so please remain a part of our community.

Finally, we’re only a little more than a month away from the 24th Annual Meeting! Abstract notifications have gone out and we could not be more excited to learn about the latest research from your excellent collection of presentations this year. Make sure you secure your spot at the meeting by registering today. Associate Members can register for free!

I hope to “see” you all virtually at the meeting!

Take care,

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

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Breaking Through


Long-Term Stable Reduction of Low-Density Lipoprotein in Nonhuman Primates Following in Vivo Genome Editing of PCKS9

Wang L, Breton C, Warzecha CC, Bell P, Yan H, He Z, White J, Zhu Y, Li M, Buza E, Jantz D, Wilson J

DOI: https://doi.org/10.1016/j.ymthe.2021.02.020

Summary by Jon Brudvig, Ph.D.

Gene editing holds great promise not only for correction of monogenic disorders, but also for  modulation of key pathways in common, complex disorders such as heart disease. By targeting the gene for PCKS9, a protein that inhibits the removal of plaque-forming LDL from the blood, gene editing could permanently reduce cholesterol levels in patients with hypercholesterolemia, greatly reducing their risk of atherosclerosis and heart disease. Several groups have demonstrated the short-term efficacy of such an approach in animal models, but a recent Molecular Therapy article from Wang et al. is the first to show that editing PCKS9 can have long lasting (3+ years) benefits in large animals.

With this study, the authors expand upon their earlier 2018 results (Wang et al. Nat. Biotechnol. 36, 717-725), and demonstrate that liver-directed AAVs encoding meganucleases that target PCKS9 can achieve long-lasting reductions in circulating PCKS9 and LDL levels. Meganucleases are homing endonucleases which recognize a relatively large recognition site — hence the name. Multiple editing approaches are in development for PCKS9-directed therapies, but this meganuclease-based approach has a distinct advantage in that the relatively small nuclease is compatible with the packaging size limits of AAV. In this study, DNA encoding the meganuclease was delivered with AAV8 or AAV3 to target hepatocytes. Two generations of the meganuclease were tested, both of which were engineered to introduce double strand breaks in the PCKS9 gene. Such breaks are repaired with the error-prone non-homologous end joining pathway, thus introducing indels that interrupt the PCKS9 gene.

Long-term results in nonhuman primates (NHPs) were encouraging. Animals that received the mid dose had sustained ~25-80% reductions in circulating PCKS9 levels and ~15-55% reductions in LDL cholesterol over 2-3+ years of follow up. Transient T cell responses to the meganuclease and increases in alanine aminotransferase (ALT) levels suggested that some transduced liver cells were targeted by the immune system shortly after administration, but the persistently high level of edited hepatocytes demonstrated that most transduced cells escaped immune-mediated destruction.  

Conventionally, immune responses against gene therapy transgenes have been thought of as serious side effects that could combat efficacy by eliminating targeted cells that are making foreign proteins. In this case, however, results suggest that immune responses may be beneficial, as they could eliminate cells that continue to express the meganuclease after the desired edits have been made, thus preventing further off-target editing. In NHPs, where meganuclease-expressing cells declined rapidly four months after administration, off-target edits were low frequency events. However, when the same vectors were tested in a parallel experiment in a liver-humanized mouse model (which by necessity lacks an immune system), edited cells persisted even when they continued to express the nuclease, leading to a much higher incidence of off-target editing.

Collectively, this study demonstrates great promise for a gene editing strategy for hypercholesterolemia. This and similar therapies will likely be tested first in patients with severe familial forms of the disease, before potentially expanding to broader sets of patients at risk for cardiac events.

From Molecular Therapy


Read these new issues of Molecular Therapy family journals:
Molecular Therapy
Molecular Therapy: Nucleic Acids
Molecular Therapy: Methods & Clinical Development
Molecular Therapy: Oncolytics

If you haven't yet, read a special issue of Molecular Therapy devoted to the topic of clinical development of gene and cell therapy. The first therapeutic use of gene transfer occurred in a trial launched in September 1990. Since then, the field has had its ups and downs. Three decades later, gene therapy has established itself as a viable therapy for numerous indications.

You can also submit your papers for a special issue of Molecular Therapy: Oncolytics on combination gene and cellular immunotherapies. These immunotherapies pose exciting regulatory challenges to the field and we’ll highlight preclinical, clinical, and regulatory advances in this special issue. More information on topics and article types is available here. Submit your paper by August 1.

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Society News


Share Our New Adenovirus-based Vaccine Resources

ASGCT has developed new educational resources to explain how the recently authorized adenovirus-based vaccine works and why it is safe and effective against COVID-19. Now available on our Patient Education site, these resources include a short videoinfographic, and answers to frequently asked questions about the vaccine. Late last year, we released similar resources on the mRNA 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!

Learn Free Tips for Virtual Meeting Success on April 16

Register for Success Strategies for a Virtual Meeting, the first in ASGCT's ongoing series of Career Development Seminars! This online seminar consists of three mini-sessions each focused on how you can stand out among potential employers and make connections during virtual meetings that can advance your career. 

Renew Your Membership and Vote for ASGCT's Future Leaders

Use your voice to help us fill four open spots on the Board of Directors who will take office on June 1. If you're a Member, Transitional Member, or Emeritus Member, you can learn more about the candidates and vote here by April 20. Your membership must be current to vote, so please renew now to maintain your ASGCT benefits! You can renew through April 30.

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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

Post your company's job here!

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Public Policy


ASGCT Applauds NINDS’ Commitment to Gene and Cell Therapies

In March ASGCT submitted feedback to the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), on its draft five-year strategic plan. ASGCT is pleased that the draft plan is supportive of the promise of gene and cell therapies. The report also highlights the burden of genetic neurological disorders which have known gene mutations but no disease-modifying therapy, and points to the importance of developing treatments for rare disorders. ASGCT’s comments focused on the need for NINDS to support and perform rigorous neuroscience research in gene and cell therapies at all levels of development. ASGCT also supported the institute’s focus on global health equity, patient engagement, workforce training and diversity, and wider communication of funding opportunities.

Society Advocates for Supplemental Research Support Funding

This month the Society continued to support supplemental NIH funding for investigators and research interrupted by the COVID-19 pandemic through a budget request to Representative Barbara Lee, who sits on the House Committee on Appropriations. The request reiterated last month’s Society support for appropriating $10 billion to NIH through a sign-on letter for the RISE Act, led by Research America.

This funding is critical to restart interrupted research, fund crucial clinical trials, and bring student researchers back to the lab so they can hone the skills needed to be future leaders in the gene and cell therapy field. The Society has advocated for this supplemental funding ever since it became clear last year that labs and clinical trial sites would experience long-term closures. With policymakers turning their attention to their goals in the post-pandemic future, ASGCT will continue to support this crucial element of the nation’s recovery.

ASGCT Launches Policy Newsletter

Last month the Society launched The Advocate, a monthly newsletter highlighting more Society actions to advance gene and cell therapies, related policy news, and analysis of effects on the field. Each issue covers a sampling of ASGCT’s advocacy efforts during the month related to our policy priorities, including regulatory and payment policy. You will also find links to register for our policy-related events.

If you would like to receive The Advocate via email every month, please contact Advocacy Program Specialist Caitlin McCombs.

Industry News


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2021

ASGCT 24th Annual Meeting

May 11-14, 2021