Volume 10, Issue 5: May 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


Thank You for Your Support

I want to thank you for your understanding and support during the 24th Annual Meeting last week. Many of you encountered technical issues, and for that I sincerely apologize. Please remember that registered attendees have access to all the sessions on demand through June 13 on the meeting platform. The content is also available for you to watch on ASGCT.org. While the technical issues were irritating, they could not and did not eclipse the more substantive, lasting, and meaningful aspects of the event which was, in my view, the best we have yet had. As you watch those on-demand sessions, I hope they inspire and energize you to carry on your work in gene and cell therapy.

I could have never imagined the pandemic-related challenges my year as ASGCT president would bring, but the past year has given me so much hope for the future of our Society and for the field in general. Together, our members, leaders, and the scientific community at large stepped up to help overcome these challenges. While adapting to the difficult circumstances of the pandemic, we organized a symposium to provide accurate scientific information straight from the people working on COVID-19 vaccines and treatments. We distributed resources explaining the mRNA and adenovirus-based vaccines. And we committed to promoting justice and equity in the field by creating funding opportunities to support underrepresented populations as well as research for conditions that disproportionately affect minorities. There is so much more work to do, but I’m honored that I’ve been able to be a part of these accomplishments while serving as president of ASGCT.

With that said, I’m pleased to introduce our next president, Beverly Davidson, Ph.D. Dr. Davidson is director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics and chief scientific strategy officer at Children’s Hospital of Philadelphia. She is an exceptional leader who has been an active member of ASGCT since the Society’s founding, so please join me in welcoming and congratulating her!

Thank you all for everything this past year, and stay well for when we can meet in person again soon!

 

Sincerely,

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

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Breaking Through


Co-opting Regulation Bypass Repair as a Gene Correction Strategy for Monogenic Diseases

Hu J, Bourne RA, McGrath BC, Lin A, Pei Z, Cavener DR

DOI: https://doi.org/10.1016/j.ymthe.2021.04.017

Summary by Karen Bulaklak, Ph.D.

In the gene therapy field, overexpression of therapeutic coding sequences is a tried-and-true method to compensate for disease-causing mutations. While effective, this approach cannot replicate the complex temporal, spatial, and quantitative expression profile associated with a normal gene. Using CRISPR/Cas9-based editing, the genome can be directly modified, preserving the natural context of a particular locus. To this end, several labs have shown that CRISPR-mediated gene knock-in is possible in mouse models. Earlier iterations take advantage of the host homology directed repair (HDR) pathway, which is not active in post-mitotic cells. More recently, insertion of larger DNA fragments in post-mitotic cells has been achieved using homologous-independent targeted insertion, or HITI. This approach involves CRISPR-mediated cutting of the endogenous target region as well as a double stranded template and relies on the non-homologous end joining (NHEJ) DNA repair pathway to attach the heterologous DNA together. Therapeutic application has largely focused on specific disease-causing mutations, requiring extensive engineering that may ultimately benefit a small fraction of the patient population.

In a recent report, Hu et al at Pennsylvania State University describe a versatile therapeutic strategy where HITI is used to insert a coding sequence (CDS) and transcription/translation terminators, which they called “Co-opting Regulation Bypass Repair,” or CRBR. This integrated cassette provides a functional copy of the gene, while exploiting endogenous regulatory regions and inhibiting read through of a disease-causing mutation. To demonstrate the potential of this approach, the authors designed a cassette encoding several exons of eukaryotic translation initiation factor 2 alpha kinase 3 (Perk), which is important for pancreatic beta cell function. Cas9 and guide RNA targeting the 5’ UTR of the Perk gene along with the partial CDS were delivered to a cell line harboring an amenable Perk deletion. After treatment, the cassette was successfully inserted, restoring protein expression. However, they note that this approach can potentially introduce cryptic splice sites. Alternatively, a cassette containing a full-length CDS was validated in vitro and used to treat Perk KO mice in utero. Plasmid microinjection of CRBR components into Perk KO zygotes resulted in robust expression from the endogenous promoter, resulting in phenotypic restoration. To visualize and replicate a more realistic application, a CRBR approach consisting of a GFP CDS cassette and guides targeting the 5’ UTR of the mouse Ins2 gene was generated and packaged into AAV vectors. Following delivery into Cas9-expressing mice, insertion of the CDS was achieved at low levels in the pancreas, with higher levels in the liver. Treatment with these vectors along with a Cas9-encoding vector into wild-type mice produced even lower levels of integration, possibly owing to variability of Cas9 provided in trans. Finally, to explore ex vivo editing, primary human islet cells were transfected or AAV-transduced with a CRBR approach intended to introduce a GFP reporter cassette into the insulin 5’ UTR. Considerable GFP expression was observed in treated cells and analyses confirmed integration into the insulin locus as intended.

Due to inherent biological challenges, such as limitations of endogenous DNA repair pathways, it is unclear if CRBR can induce sufficient levels of insertion and subsequent expression to confer therapeutic efficacy. Difficulties aside, the authors move beyond a highly personalized strategy characteristic of previous attempts with HITI. Such creative and broad-reaching efforts represent crucial steps in overcoming hurdles that face the gene therapy field.

From Molecular Therapy


This month, read these new issues of Molecular Therapy family journals:

You can still 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


Watch Annual Meeting Recordings On Demand

We know that many attendees were not able to consistently access content during the first two days of the meeting and for that we sincerely apologize. We appreciate your understanding and support as we worked to resolve those issues. Please remember you can watch all the sessions on demand through June 13 on the meeting platform and on ASGCT.org. Here are some other things to check out on the meeting platform.

Visit the Exhibit Hall: Check out the latest products and services in gene and cell therapy at 100 booths in the Exhibit Hall. Learn more about each company, connect with staff, and find out who's hiring!

View the Digital Poster Presentations: Search 565 digital posters by category or author. You can also connect with authors directly by emailing them or using the chat feature.

Apply for CDA and New Diversity and Inclusion Awards June 1 

Between June 1 and August 1, you can apply for the Career Development Awards and our new Diversity and Inclusion Awards. The CDA values have doubled to $100,000 each in 2021, and support six members working toward independence in their gene and cell therapy careers. As part of the Society's commitment to promoting justice and equity in gene and cell therapy research, we have created three new Diversity and Inclusion Awards totalling $250,000. You can find more information about all of these awards here.

Congratulations to Our New Board Members

Please welcome four new members of the ASGCT Board of Directors who will take office on June 1. We are thrilled to introduce Jeffrey Chamberlain, Ph.D., Rayne Rouce, M.D., Hildegard Büning, Ph.D., and Maria-Grazia Roncarolo, M.D. These new members will serve three-year terms and the incoming Vice President will ascend through the presidential succession process before serving as ASGCT President in 2023-24. Read more about them here.

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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 Supports Federal Action on Gene Therapies

This month, the TRANSPLANT Act (HR 941) passed the U.S. House of Representatives and was referred to the Senate. The bill would reauthorize the C.W. Bill Young Cell Transplantation Program. Significantly, the legislation includes ASGCT-recommended language to codify attention to regenerative medicine into the Public Health Service Act (PHSA) and to explicitly include gene therapies and genetically-modified cells in the definition of regenerative medicine.

Also this month, ASGCT highlighted to federal policymakers the critical importance of NIH funding for gene and cell therapy researchers in fiscal year (FY) 2022. The Society encouraged two US Representatives to sign on to a letter requesting appropriators to fund NIH at a level of at least $46.1 billion in FY22, an increase of $3.2 billion above the FY21 level. ASGCT reached out to Congresswoman Barbara Lee, who sits on a key House Appropriations subcommittee, and Congressman Scott Fitzgerald, who represents the area in Wisconsin where ASGCT has its executive offices.

Society Supports Access to Newborn Screening

ASGCT supported language in the Ohio state budget (HB110) last month that would expand and accelerate newborn screening (NBS) in Ohio. The bill would add SMA and X-linked adrenoleukodystrophy to Ohio’s state NBS panel. The state would also be required to expeditiously consider screening for any condition that is added to the federal Recommended Uniform Screening Panel. HB110 passed the Ohio House of Representatives and has been referred to the Ohio Senate. ASGCT supported this legislation via an EveryLife Foundation sign-on letter.

Register for the Forum on Gene Therapy for Underserved Populations

ASGCT is hosting a free, virtual event on Tuesday, June 22, focusing on gene therapy drug development for people with ultra-rare diseases and those in lower-income countries. Speakers from leading efforts in this space will identify the scope of development; discuss innovative approaches and business models; and spark conversation to advance these treatments. Learn more and register for this event.

Industry News


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