The Vector

Volume 11, Issue 1: January 2022


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


Free Virtual Series Explores Long COVID and International Trainees


Happy New Year, ASGCT Members,

I hope you had a restful holiday and start to the new year, and that you’re continuing to stay safe and healthy. We have a lot happening at ASGCT in 2022 and I’m looking forward to working with many of you on our new programming and initiatives. In fact, registration is now open for the first two sessions of ASGCT’s Insight Series, a new series of two-hour virtual events that begins later this month and will be free for ASGCT members.

On Jan. 25, join us for the first session of the series, Clinical Aspects and Immune Responses in Patients with Long COVID-19. Our speakers will give a general overview of the pathogenesis of COVID-19, describe clinical aspects of long COVID, discuss immune responses in patients with long COVID, and address how neurological damage caused by the virus may contribute to persisting symptoms. The second session, Finding a Good Match - Landing a Perfect Position in an International Lab, will be held Jan. 26. During this session, attendees will learn best practices around finding employment and hiring non-U.S. based PhD students and postdoctoral fellows to the U.S. Feel free to pass along information about this series to your colleagues who may be interested; non-members can attend for $50 or they can join ASGCT to attend for free.

Next week, I hope you’ll attend our free monthly Professional Development Café, “How To” with CAR T-Cell Therapy, on Jan. 21. Our speaker will be Stephen Gottschalk, MD, a faculty member and chair of the department of bone marrow transplantation and cellular therapy at St. Jude Children's Research Hospital. Register now to expand your knowledge on CAR T-cell therapy and bring your questions for Dr. Gottschalk.

If you haven’t done so yet, make sure you also register for the 25th Annual Meeting. On May 18, we’ll hear from our plenary speakers: Drew Weissman, MD, PhD, will present the George Stamatoyannopoulos Memorial Lecture; Francis Collins, MD, PhD, will present the Founders Award Lecture; and Kathy High, MD, will present Presidential Lecture. Abstract submission is open through Feb. 2, so please send us your research for a chance to present your work.

Sincerely,

Beverly L. Davidson, PhD
ASGCT President

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Breaking Through


Cell-Penetrating Peptide-Conjugated Morpholino Rescues SMA in a Symptomatic Preclinical Model

Bersani M, Rizzuti M, Pagliari E, Garbellini M, Saccomanno D, Moulton HM, Bresolin N, Comi GP, Corti S, Nizzardo M

DOI: https://doi.org/10.1016/j.ymthe.2021.11.012

Summary by Jon Brudvig, PhD

Efficient delivery is a persistent challenge for genetic therapies. Viral vectors have restricted tropism patterns driven by their dependence on receptor-mediated internalization. Antisense oligonucleotides (ASOs) and other oligo-based therapies have similar limitations driven by tissue penetration and cellular uptake. Even small molecule modulators of splicing and translation have limited biodistribution in some tissues and cell types. These limitations have led to a renewed focus on improving delivery with a variety of approaches showing promise. Here, Bersani, et al. demonstrate that ASOs for spinal muscular atrophy (SMA) can be improved by conjugation with cell-penetrating peptides (CPPs), which enhance systemic delivery and markedly improve efficacy, even in a challenging postsymtomatic model.

SMA is autosomal-recessive, degenerative motor neuron disease caused by mutations in the SMN1 gene. Humans have a paralog of SMN1, SMN2, that usually fails to include exon 7, resulting in a nonfunctional, truncated protein product. Modulation of splicing has long been an appealing SMA drug target, as inclusion of exon 7 can restore SMN protein production to disease-modifying levels. Nusinersen, an ASO designed to correct SMN2 splicing, was the first approved drug for treating SMA following FDA approval in 2016. While efficacy has been impressive, nusinersen cannot cross the blood-brain barrier and therefore must be administered by repeated intrathecal injections, which are frequently accompanied by side effects. Even when administered in this way, biodistribution is limited by patterns of CSF flow and penetration is likely incomplete in some regions of the brain and spinal cord. An ASO that could efficiently penetrate the CNS following intravenous administration could thus improve safety, reduce treatment burden, and even enhance efficacy for individuals living with SMA.

CPPs have recently emerged as useful conjugates for improving ASO delivery. CPPs are small, arginine-rich, cationic peptides that facilitate delivery of diverse cargoes across cellular membranes and barriers to biodistribution (such as the blood brain barrier). In the present study, the authors compare unconjugated ASOs with ASOs conjugated to several well-characterized CPPs in a mouse model of SMA. When delivered by IV injection, only the CPP versions crossed the blood-brain barrier and restored SMN expression to therapeutic levels. One of the CPP conjugates, “r6-MO,” was able to correct a wide range of phenotypes even when delivered at the postsymptomatic stage of postnatal day five. Compared to treatment with the unconjugated version, r6-MO more than doubled median survival and rates of motor function preservation, presumably as a direct consequence of the improved rescue in motor neuron development and survival. The strength of these results is notable, as even intrathecally delivered therapies have generally failed to exhibit such robust postsymptomatic efficacy in prior SMA mouse studies.

It remains to be seen whether the promise of CPPs will hold in human patients. Decades of research have led to promising preclinical results for SMA and other disorders, but no CPP-containing drug has yet been approved by the FDA. Sponsors are pushing these technologies forward, however, with several CPP-containing drug candidates entering clinical trials for oncology and rare genetic diseases. Encouragingly, Sarepta recently announced early positive results in a phase I/IIa clinical trial for a CPP-conjugated ASO for the treatment of Duchenne muscular dystrophy, with data suggesting a dramatic improvement over the first-generation unconjugated version. If CPPs live up to their promise of efficient blood-brain barrier penetration and widespread distribution to target cells, the field could be nearing a major breakthrough in the delivery of genetic medicines.

From Molecular Therapy


Now open: Search for Molecular Therapy—Oncolytics editor-in-chief: ASGCT has opened its search for the next editorial leader of MTO as the inaugural editor-in-chief Dr. Yuman Fong’s term ends Dec. 31, 2022. MTO is an online, open-access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer. Its 2020 impact factor is 7.200.

Applications must include a letter of intent detailing relevant experience and vision for the journal as well as a current C.V.  Interested ASGCT members may submit inquiries to ASGCT CEO David Barrett.

Molecular Therapy—Methods and Clinical Development call for papers: Submit a paper to a special issue on evidence generation and reproducibility in cell and gene therapy research. Learn more about this special issue by reading this editorial and submit a paper by April 30, 2022.

Check out the latest issue of Molecular Therapy here, and don't miss the most recent content from other issues in the MT family:

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Society News


Register Now to Secure the Lowest Rates for #ASGCT22

The 25th Annual Meeting is the best place to learn from the latest scientific research, stay up to date on new technologies, and make career-advancing connections with gene and cell therapy professionals. Join us (safely) in Washington, D.C. or virtually May 16-19, and add a Pre-Meeting Workshop to your registration to jumpstart your learning!

Nominate a Colleague for an Annual Meeting Award

Do you know an ASGCT member who has contributed significantly to the field of gene and cell therapy? ASGCT is now accepting nominations for four prestigious Annual Meeting Awards: the Outstanding Achievement Award, the Outstanding New Investigator Award, the Sonia Skarlatos Public Service Award, and the Jerry Mendell Award for Translational Science.

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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


Attend Pre-Meeting Workshops on Trending Topics in the Field 

ASGCT will host a number of in-depth workshops on May 15, immediately preceding the 25th Annual Meeting, highlighting issues in regulatory policy, commercialization, and other hot topics in the field. Workshop registrants will have the opportunity to attend these focused sessions in a new, hybrid format.

  • The Issues and Trends in Clinical Development and Driving Standards to Accelerate Development workshops will be tailored towards regulatory professionals to discuss strategies for optimizing the clinical development of gene and cell therapies, and to explore the standards development process.  

  • Given the anticipated pipeline of gene therapy approvals, the Newborn Screening workshop will dive into the regulatory and policy issues affecting the newborn screening system in the U.S. 

  • Investigators in translational sciences will not want to miss the Early-Stage Development workshop, where experts will address key topics in early-stage cell and gene therapy development. The AAV Integration workshop will bring together leaders in the field to discuss the knowns and unknowns of AAV vector integration and regulatory implications for the field. 

Check out the complete list of workshops and register to attend here. In our new hybrid format, you can register as a virtual or in-person attendee, with all sessions recorded and available on demand following the event. 

Now Available: ASGCT-Supported Newborn Screening Modernization Study

In 2020 ASGCT joined the advisory board for a study conducted by RTI International on newborn screening (NBS) modernization. The first paper to come of that effort, Expert Evaluation of Strategies to Modernize Newborn Screening in the United States, was recently published. To obtain access to, and maximal benefit from, potentially life-altering gene therapies either in clinical trials or post-approval, diagnosing patients as early as possible is critical. ASGCT will continue to support an effective, modern NBS system as part of the Society’s strategic priority to support timely patient access to innovative treatments. 

2022

ASGCT 25th Annual Meeting

May 16-19, 2022

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