The Vector

Volume 13, Issue 2: February 2024


Editorial Team

Jon Brudvig, PhD – Editor, The Vector
Jessica Schneller, PhD – Associate Editor, The Vector
Wan Du, MD, PhD – Junior Editor, The Vector

Inside This Issue

Leadership Message
Breaking Through
From Molecular Therapy
Society News
Career Center
Public Policy
Industry News

Leadership Message


Final Weeks to Receive Lowest Rates to #ASGCT2024

Hello ASGCT members,

I hope you’re looking forward to an exciting collection of research that will be presented at the 27th Annual Meeting! We asked for your CGT work, and as always, you delivered. That’s all we can say while our committee volunteers work to review this year’s submissions, but just know you won't want to miss this meeting. Presenters will be notified by March 25, but in the meantime, check out our online program, which is updated daily with confirmed speakers. Search the program by day, session type, keyword, and more to plan your time at the Annual Meeting in Baltimore or virtually, May 7-11.

Join us for the first time in Charm City! Make sure you’re registered by Feb. 29 to secure the lowest rates. We’re heading back to the East Coast for more than four full days of the latest scientific discoveries, perspectives from the experts, networking and career development opportunities, half-day workshops, and so much more. Add on a workshop, book your hotel, or  snag a spot for the Closing Night Reception on our website while space is available.

The call for late-breaking abstracts opens Monday, Feb. 19. If you have data is that is high-impact, groundbreaking, innovative, and newsworthy, submit it to us for the opportunity to present your work at the meeting. Only abstracts presenting data that is truly “late breaking” will be considered. Also, there will not be a late breaking poster session, so only those abstracts selected for talks will be presented at the conference. Submissions are open through March 8. 

Finally, don’t forget to renew your membership! Maintain access to benefits like discounted registration for the Annual Meeting and other year-round events, a subscription to and publishing opportunities in Molecular Therapy, on-demand access to professional development opportunities, and more. Stay connected to the largest global community of gene and cell therapy researchers and renew today.

 I'll see you in Baltimore soon!

Jeffrey S. Chamberlain, PhD
ASGCT President

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Breaking Through


A cardiotoxicity-eliminated ACE2 variant as a pan-inhibitor against coronavirus cell invasion

Feng H, Yang L, Yang H, Cheng D, Li M, Song E, Xu T

DOI: https://doi.org/10.1016/j.ymthe.2023.11.019

Summary by Jessica Lee Schneller, PhD

Identifying an antiviral medication that could be effective against all severe acute respiratory syndrome coronavirus (SARS-CoV-2) variants is a critical step in the ongoing development of vaccines to combat coronavirus disease 19 (COVID-19). An increasing number of new SARS-CoV-2 variants are evolving that escape vaccine protection, yet the development of drugs against COVID-19 has slowed. Soluble human recombinant angiotensin I converting enzyme 2 (hrACE2) has demonstrated clinical efficacy for severe COVID-19 in decreasing viral load and attenuating inflammatory injury. Overexpression of hrACE2, however, can promote fibrogenesis and lead to fatal and irreversible cardiac injury in healthy individuals. In this study by Feng et al., the authors sought to demonstrate that an hrACE2 mutant could effectively block variant coronavirus cell invasion as well as wild-type (WT) hrACE2, but without the cardiac toxicity associated with the WT enzyme.

ACE2 is the mutual receptor for a series of coronaviruses and is necessary for cell invasion. Initial studies aimed to demonstrate that angiotensin-converting enzymes (ACEs) are highly expressed in human lung cells, and that several coronavirus strains enter cells via this receptor. Studies in which ACE2 was overexpressed in a BEAS-2B human lung epithelial cell line showed increased cell entry of the spike protein (SP) of seven different coronavirus strains. Extracellular delivery of hrACE2 blocked the entry of the SP receptor binding domain (RBD) of the seven coronaviruses, suggesting it might work as a pan inhibitor against coronavirus cell entry. To analyze the effects of hrACE2 in vivo, the SP variants of several coronaviruses were purified from mammalian cells and delivered in Syrian golden hamsters by nasal drop. 24-hour exposure to these SP variants induced the early stages of pneumonia, with thickened alveolar septum and inflammation in the lung; but pretreatment with hrACE2 fused to mouse Fc (hrACE2-mFc) blocked S protein entry into lung cells, reduced inflammatory cytokines, and reversed T cell and macrophage recruitment. Thus, it was demonstrated that free hrACE2 could potentially work as a pan-inhibitor in vitro and in vivo against cell entry from diverse coronaviruses using ACE2 as the entry receptor.  

To determine whether the adverse cardiovascular effects induced by hrACE2 might be caused by its Zn2+ structural activity, the authors generated a series of hrACE2 mutants. These variants contained different combinations of mutations in the 4 histidine residues acting as the core of ACE2 enzyme activity. While the different variants showed variable levels of enzyme activity and SP binding affinity, only the tetrad mutants could not induce degradation of Ang II. Extracellular degradation of Ang II is believed to be partially mechanistically responsible for the cardiotoxicity associated with ACE2 over-expression. To investigate efficacy in vivo of the tetrad mutant (hrACE2-4mu), it was fused to mouse Fc (hrACE2-4mu-Fc) and injected into FVB mice daily for a month. Compared to mice treated with hrACE2-mFc, hrACE2-4mu-Fc treated mice demonstrated complete reversal of the adverse cardiac effects associated with the non-mutated ACE2 while maintaining full enzymatic activity.

To assess the capability of the hrACE2-4mu to occlude the SPs of WT and other SARS-CoV-2 variants, the different mutated ACE2 variants were delivered to BEAS-2B cells. Notably, hrACE2-4mu showed the same ability to block cell entry of SPs and pseudo-virus as WT hrACE2. To establish efficacy of hrACE2-4mu against coronavirus SP in vivo, hrACE2-4mu-Fc was administered to hamsters by intraperitoneal injection, and lung tissues were collected after 24 hours of SP and hrACE2-mFC pre-treatment. Compared with the effect of hrACE2-mFC, pretreatment with hrACE-4mu-mFc ameliorated lung weight, alveolar expansion, and inflammatory cell infiltration. In addition, hrACE2-4mu-mFc reduced inflammatory cytokine levels induced by SP nasal drop, and these protective effects were comparable to the effect of hrACE2-mFc on guinea pigs. In conclusion, the authors generated a novel ACE2 variant, ACE2-4mu, and demonstrated its ability to block cell invasion by a series of coronaviruses as effectively as the WT ACE2 but without the severe cardiac side effects observed after WT ACE2 administration.     

From Molecular Therapy


On the Molecular Therapy Podcast: Dr. Richard Vile discusses a recent article published in Molecular Therapy Oncology by himself and colleagues titled, "Trap and ambush therapy using sequential primary and tumor escape-selective oncolytic viruses."

Active Calls for Papers

RNA and epigenetic editing: A new generation of precision therapeutics 

Novel therapeutic targets and biomarker development 
 

Latest MT issues: Check out the most recent issues of these Molecular Therapy family journals:

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Society News


Next Friday: Free Café on AI in Gene and Cell Manufacturing

Join speaker Claire Aldridge, PhD (Form Bio), and moderator Li Ou, PhD (Avirmax, Inc.), for our February Professional Development Café! Dr. Aldridge will discuss how today's powerful computational tools can provide key insights into manufacturing to improve the efficacy and safety of these therapies. Register here.

Plan Your Time at the 27th Annual Meeting

Set up your Annual Meeting schedule with our daily updated, interactive agenda. Search by session type, presenter name, day, and more. Register through Feb. 29 for the lowest rates!

New Blog: Biden-Harris Administration Announces New CGT Payment Model

Check out a new blog post on the recently announced cell and gene therapy (CGT) access model from ASGCT's Director of Policy & Advocacy Margarita Valdez Martínez. The model will enable CMS to negotiate outcomes-based agreements with manufacturers.

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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.

 

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Public Policy


FDA Requesting Industry Nominations for CGT Advisory Committee 

The FDA is seeking industry organizations interested in participating in the selection of a nonvoting industry representative for the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC). They are also accepting nominations for nonvoting industry representatives, which can be self-nominated or nominated by an organization. The CTGTAC evaluates data on the safety and effectiveness of human cells, tissues, gene transfer therapies, and xenotransplantation products. Additionally, it reviews the quality and relevance of FDA's research program supporting the regulation of these products and makes recommendations to the Commissioner of Food and Drugs.  

Nomination materials for prospective candidates should be sent to FDA’s online portal by February 22.

Senate Committee Leaders Seek Information on Patient Access to CGTs 

Ranking Member Bill Casidy of the Senate’s Health, Education, Labor, and Pensions Committee recently released a request for information on improving access to gene therapies; ASGCT’s response focused on several key themes. The Society continuously advocates for policies that can improve patient access to gene therapies. A previously-published paper highlighted disparities in state Medicaid practices for cell and gene therapy coverage. In the RFI response, ASGCT urged specific federal action to ensure equitable access for patients on Medicaid, and noted that attention was needed to ensure similar access barriers are addressed in the commercial insurance market. The letter also underscores the importance of prompt coverage of therapies upon FDA approval, which can be supported by early coordination between FDA and CMS. Additionally, ASGCT’s comments highlighted the need for flexibility in regulatory frameworks for developing gene therapies, and alternative development pathways for individualized ultra-rare diseases. The Society noted that there are unique challenges for rare and ultra-rare disease development that have to be considered. As conversations continue in this space, ASGCT will keep advocating for policies that can facilitate the development and accessibility of transformative treatments. 

Continuing Resolution Extends Funding Deadlines for FDA and NIH  

A government shutdown was averted on Friday, January 19, when President Biden signed into law the Further Additional Continuing Appropriations and Other Extensions Act, 2024. This continuing resolution (CR) will temporarily fund the federal government at fiscal year 2023 levels. Federal agencies and government activities are funded in four appropriation bills through March 1, and eight appropriation bills, and related agencies, are funded through March 8.  

FDA’s current funding is now set to expire on March 1, leaving researchers and scientists in a state of uncertainty; NIH is currently funded through March 8. Legislators must work to reconcile these spending bills before their due dates. If these funding deadlines are not met, and a CR is still in place by April 30, automatic spending cuts would be triggered. This sequestration procedure could cut federal funding by 1% across the board. 

Appropriation bills had stalled as legislators reviewed foreign aid packages for Ukraine, Israel, and Taiwan. Attempts to tie foreign support to border provisions led to negotiation stalemates and pushed appropriators up against tight funding deadlines. The current CR contains several policy riders that delayed the passage of the funding extension until just before the deadline.These include amendments on issues such border protection, abortion, and gun control.  

ASGCT will continue to watch the federal funding process and engage to ensure robust federal funding for CGT research and development programs.   

CMS Issues New Prior Authorization Regulations 

The Centers for Medicare & Medicaid Services (CMS) issued a final rule on prior authorization policies. Notably, this will impact Medicaid managed care plans. The overuse of prior authorization has been cited as a barrier for Medicaid beneficiaries in receiving access to cell and gene therapies. 

Key changes starting in 2026 include: 

  • Faster Prior Auth Decisions: Medicaid managed care plans must issue decisions within seven days for standard requests and 72 hours for expedited requests, streamlining access to potentially lifesaving therapies. 

  • Reason for Denial: All impacted payers will have to issue a specific reason for denial of a prior authorization request. This will be issued through notifications to providers.  

  • Metrics: All impacted payers will be required to publicly report on prior authorization metrics similar to the ones already used for Medicare FFS. ASGCT also recommended the creation of a public dashboard to track coverage and denials. 

These changes are significant wins for the gene and cell therapy community because faster prior authorization decisions and streamlined processes will reduce treatment delays and improve patient access to these often-curative therapies.  

Global Pilot Launched for Gene Therapy Collaboration

Peter Marks, director of FDA’s Center for Biologics Evaluation and Research (CBER) outlined plans for a pilot program to explore the possibility of a collaborative review process for new gene therapy applications with other global regulators. Marks shared that the Collaboration on Gene Therapies Global Pilot (CoGenT) would include initially include regulatory members of the International Council for Harmonisation. The goal of the pilot is to increase global harmonization by increasing efficiency in reviews of gene therapies and reducing delays in bringing these therapies to market. 

Industry News



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2024

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May 7-11, 2024 | Baltimore, MD

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