The Vector
Editorial Team
Karen Bulaklak, PhD – Editor, The Vector
Jon Brudvig, PhD – Associate Editor, The Vector
Jessica Schneller, 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
Still Time to Register for Our First-Ever Immuno-Oncology Conference
Hello, ASGCT members,
I hope you’re all having a good summer. We’re less than three weeks away from the inaugural Spotlight on Immuno-Oncology Conference if you’d still like to attend in person in Seattle or virtually. You’ll hear from experts including Carl June, MD; Michel Sadelain, MD, PhD; Paula Cannon, PhD; and more, who will help us dig into the intersection of gene engineering and gene and cell therapy. Check out the program and abstracts collection and make sure you register to learn more during the event Aug. 1-2. We’re really looking forward to exploring novel CAR designs, progress in immunotherapy, B cell malignancies, and more with the best in the field!
Also coming up on Aug. 1 is the deadline to apply for our Career Development Awards (CDAs) and our Diversity, Equity, & Inclusion (DEI) Awards. If you’re interested in funding a transformative pilot study, apply for one of our six CDAs ($100,000 each) to help you gain career independence. This year, the Children’s Tumor Foundation is supporting three additional CDAs. If you’re a member who is part of an underrepresented minority population or group in the scientific workforce, apply for one of our DEI Awards. We’re offering three DEI Awards totaling $250,000 for both members from underrepresented groups and for members conducting research on conditions that disproportionately affect minority populations.
Finally, I wanted to point out that this past month has been an exciting one in CGT news, as there were two new gene therapies approved by FDA. Elevidys became the first gene therapy to be approved for Duchenne muscular dystrophy. Just one week later, Roctavian became the first FDA-approved gene therapy for adults with severe hemophilia A. I’m so thrilled for the patients and families who will be able to live longer, fuller lives because of these new treatments, and I look forward to more approvals in the coming months.
Take care and I hope to see you in Seattle next month.
Jeffrey Chamberlain, PhD
ASGCT President
Breaking Through
Genome editing in the mouse brain with minimally immunogenic Cas9 RNPs
Stahl, EC, Sabo JK, Kang MH, Allen R, Applegate E, Kim SE, Kwon Y, Seth A, Lemus N, Salinas-Rios V, Soczek KM, Trinidad M, Vo LT, Jeans C, Wozniak A, Morris T, Kimberlin A, Foti T, Savage DF, Doudna JA
DOI: https://doi.org/10.1016/j.ymthe.2023.06.019
Summary by Karen Bulaklak, PhD
Despite recent therapeutic wins in the neurological disease space, delivery to the CNS remains a challenge for the gene therapy field. For early preclinical work, many groups have resorted to more invasive procedures, such as stereotactic injection into the brain, especially for hard-to-reach cell types. As interest and applications for genome editing for neurological diseases continue to build, sufficient delivery again poses an obstacle and may preclude exploration into newer therapeutic modalities and amenable diseases. AAVs are commonly utilized for CNS delivery; however, they may not be the most desirable for genome editing. The AAV transgene cassette cannot be easily changed to adapt to every patient mutation and AAVs are laborious to produce. Furthermore, AAV-based therapies generate an immune response against the capsid and vector integration into the host genome has been observed in preclinical studies. To circumvent these issues, Stahl et al from Jennifer Doudna’s laboratory created and characterized a CRISPR ribonucleoprotein (RNP)-based system for use in the CNS.
The group of researchers first designed different constructs to enable greater delivery of the Cas9 and to compare with AAVs in the Ai9 reporter mouse. In this system, Cas9 and a single guide RNA are delivered to create cuts in the genome to allow reporter expression. Both RNPs and AAVs were able to induce reporter expression in cells isolated from Ai9 mice, and they found that including more repeats of the SV40 nuclear localization (SV40-NLS) peptides onto the Cas9 increased editing at the EMX1 locus in human neural precursor cells when delivered as RNPs. The researchers next compared administration routes in vivo with RNPs, and found that each route of administration resulted in a different gene editing profile. Using convection enhanced delivery (CED) of RNPs into the striatum resulted in robust editing, which extended into the globus pallidus and substantia nigra. In a head-to-head comparison with AAVs, the RNPs produced about half the reporter-positive area (47% and 22% for AAV and RNP, respectively) and less gene editing measured via an NHEJ ddPCR readout (15% and 2% modification for AAV and RNP, respectively). Interestingly, Cas9-RNPs edited more NeuN-positive neurons compared to Cas9-AAV (36% vs. 20%, respectively) and the inverse was true for glial cells (2% and 8% for RNP and AAV, respectively). The group explored the immune response after RNP and AAV delivery, and found that RNPs induced both a cellular and humoral immune response that was dose dependent. Higher levels of anti-Cas9 IgG were observed compared to AAV delivery, which decreased over time. Finally, both RNP and AAVs induced similar expression changes of selected immune markers at the site of injection.
In summary, this report presents an alternative to AAV-based delivery for genome editing into the CNS. Further delivery optimization, such the strategy as described in this report, could hopefully expand the range of therapeutic approaches to meet the needs of patients.
From Molecular Therapy
Apply to Be Next Editor of MTMCD
ASGCT is looking for the next editor-in-chief of Molecular Therapy - Methods & Clinical Development (MTMCD) to begin a five-year term Jan. 1. Learn more + apply here.
Latest MT issues: Check out the most recent issues of these Molecular Therapy family journals:
Molecular Therapy (July 5)
Molecular Therapy—Oncolytics (June 15)
Molecular Therapy—Nucleic Acids (June 13)
Molecular Therapy—Methods and Clinical Development (June 8)
Society News
Final Weeks to Apply for More than $1 Million in Awards
All members are eligible to apply for a Career Development Award or a Diversity, Equity, & Inclusion Award through Aug. 1! We're giving out more than $1 million in funding to help you grow your career through your research; check out the descriptions for each award here and apply today. Watch this video to learn how it can help your career.
Explore Immuno-Oncology Abstracts Ahead of Inaugural Meeting
Before you head to next month's Spotlight on Immuno-Onology Conference, check out the latest reserach that will be presented at the meeting. Read the most innovative science on novel CAR designs, cancer immunotherapy, B cell malignancies, genome and epigenome editing, and more. Make sure you're registered to join us Aug. 1-2.
Read the Q2 Landscape Analysis Field Report
The second quarterly report of 2023 from ASGCT and Citeline is available now! In Q2, six therapies were approved, including two gene therapies that were the first to be approved for their respective indications, Duchenne muscular dystrophy (DMD) and dystrophic epidermyolysis bullosa (DEB). Read and download the report here.
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 5,500+ audience of The Vector.
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Public Policy
Society Partners with Advocacy Groups to Voice NTAP Concerns to CMS
The Society has submitted comments to the Center for Medicare and Medicaid Services (CMS) on the FY24 Inpatient Prospective Payment Systems (IPPS) Proposed Rule. Comments asked CMS to reconsider their suggested modifications to the eligibility requirements for a special payment program called New Technology Add-on Payment (NTAP). ASGCT emphasized the importance of alternative approaches, predictability, and innovative payment models to ensure that patients can easily access novel cell and gene therapies (CGT). The Society also partnered with patient advocacy groups to express concerns about the potential negative impact of reducing the duration of NTAP on patients' access to these therapies.
One specific concern raised was CMS' proposal to establish an earlier deadline for products to qualify for NTAP once they receive marketing authorization. Limiting access to NTAP could have disastrous consequences for patients, particularly those relying on new CGT products. Comments also addressed changes to how a specific measure, the relative weight of MS-DRG 018, is calculated. ASGCT encouraged CMS to continue excluding cases related to clinical trials and expanded use for immunotherapy. The Society appreciates CMS for recognizing the unique nature of CGTs, and emphasized the need for a predictable payment policy to facilitate the introduction of these therapies to the market.
Comments to FDA Exmphasize Flexibility in Post-Approval Data Requirements
ASGCT recently provided feedback to FDA regarding the methods and approaches used to gather information on the safety and effectiveness of cell and gene therapy products after they have been approved. In the comment letter, ASGCT highlights important points discussed in a public FDA listening session and emphasizes the benefits of alternative study designs, such as decentralized trials, in speeding up the development and adoption of CGT therapies. ASGCT stresses that embracing these approaches can improve patient access and allow a more diverse population to participate, leading to results that are more representative and applicable to a broader range of individuals. Additionally, decentralized study designs enable data collection in natural environments, providing a more accurate understanding of treatment outcomes and long-term safety.
ASGCT also emphasizes the significance of establishing registries specific to products and diseases. These registries act as large databases that gather real-world data on the safety and effectiveness of medical products and treatments. Unlike controlled clinical trials, these registries offer valuable insights into how therapies perform in real-world settings, disease progression, and overall patient outcomes. ASGCT believes that utilizing real-world evidence can better inform treatment decisions, and future research can be guided more effectively.
Appropriations for FDA Move Through Congress
Last month, a deal was reached to increase the federal debt ceiling for the next two years. However, concerns have been raised by researchers and health care advocates regarding the impact of this deal on research and development. The agreement imposes a freeze on non-defense and veterans' health spending at 2023 levels for the upcoming year, with only a 1% increase allowed in 2025. Some lawmakers in charge of appropriating funds have noted this 1% increase is a ceiling rather than a floor, indicating the possibility of deeper cuts in funding.
These potential cuts could severely impact the National Institutes of Health (NIH), which has seen consistent growth over the years and plays a crucial role in funding research for diseases like cancer, Alzheimer's, and rare conditions. Furthermore, President Biden's initiatives, such as the Cancer Moonshot and the Advanced Research Projects Agency for Health, may face funding limitations under this new agreement. This raises concerns among disease advocacy groups and research organizations about potential setbacks to scientific progress.
For fiscal year (FY) 2024, FDA requested a total of $7.2 billion in annual funding. This represents an increase of $372 million from FY23, around 10%. On June 14 the House Committee on Appropriations advanced an allocation of $6.5 billion, rolling back the amount to the same level as FY23. Meanwhile the Senate Appropriations Committee advanced S.2131 on June 22, which includes an increase of $20 million over FY23 levels. The Society will continue to watch the appropriations process, specifically looking at the impact to FDA, NIH, and other agencies affecting ASGCT members.
Apply for Rare Disease Endpoints Advancement Program
FDA has launched a new initiative called the Rare Disease Endpoints Advancement (RDEA) pilot program. This program is now accepting applications from sponsors who want to develop therapies for rare diseases. The goal of the program is to encourage collaboration between sponsors and FDA during the development of novel endpoints to measure how effective treatments are for rare diseases, including those affecting children. FDA will organize workshops, release guidance documents, and train its staff to better support the use of these new methods for evaluating the effectiveness of rare disease treatments.
The RDEA pilot program began in October 2022 as part of FDA's commitment to improving rare disease drug development. Sponsors with active investigational new drug applications (INDs) or pre-INDs related to rare diseases are eligible to participate. Recently, the FDA updated its webpages, including an FAQ page, to provide more information and guidance for companies interested in joining the RDEA pilot program. The webpages include details about submission deadlines, what to include in proposals, and requirements for meeting requests and package submissions.
Industry News
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