The Vector

Volume 10, Issue 7: July 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


There's Still Time to Apply for ASGCT Funded Awards


Hello ASGCT Members,

I want to start off by saying thank you for giving me this wonderful opportunity to serve as ASGCT President! My name is Beverly Davidson and I’m the director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia and professor of pathology & laboratory medicine at the University of Pennsylvania. My research focuses on inherited genetic diseases that cause central nervous system dysfunction, both recessive, childhood onset and dominant neurodegenerative diseases. I work on gene therapy approaches to try and impact the onset and progression of these disorders through vector and cargo development. I have been a proud member of ASGCT since its founding in 1996 and served in various roles to help the Society accomplish its missions, and I look forward to working with leadership, staff, and many of you this year to move the Society and the field forward.

I’m pleased to announce that this year, ASGCT will offer more events and opportunities than ever before. Tomorrow we’re holding our next Professional Development Seminar, “How To” With AAV Vectors, which is free and will be available on demand for ASGCT members. Next week, registration will open for the 2021 Policy Summit, which will be held September 22-24 both in person and virtually in Washington D.C. The Summit will offer a variety of stakeholder perspectives on hot topics in the gene therapy field and how they inform regulatory, legislative, and payment policies for diagnosis and treatment. More information will be added to the website as it’s confirmed.

Another important note is that we are in the middle of award season! Please peruse our award opportunities and apply! We have six Career Development Awards that have been doubled this year as well as four new Diversity & Inclusion Awards. Please pass these opportunities along to other ASGCT members (or potential members) in your networks!

Finally, there is a little more than one month left to watch on-demand content from the 24th Annual Meeting, which is available on the meeting platform and on ASGCT.org for registered attendees. I hope you’ll take advantage of this, as there were so many informative and exciting presentations that were difficult to catch during the virtual event.

 

Sincerely,

Beverly L. Davidson, Ph.D.
ASGCT President

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Breaking Through


Predicting Genotoxicity of Viral Vectors for Stem Cell Gene Therapy Using Gene Expression-Based Machine Learning

Schwarzer A, Talbot S, Selich A, Morgan M, Schott J, Dittrich-Breiholz O, Bastone A, Weigel B, Ha TC, Dziadek V, Gijsbers R, Thrasher A, Staal FJT, Gaspar HB, Modlich U, Schambach A, Rothe M

DOI: https://doi.org/10.1016/j.ymthe.2021.06.017

Summary by Jon Brudvig, Ph.D.

Ex vivo hematopoietic stem cell (HSC) gene therapy shows great promise as a treatment for a growing variety of human diseases. With this therapeutic modality, autologous hematopoietic stem cells are harvested from the bone marrow or peripheral blood, genetically modified, and reintroduced into a preconditioned patient where they engraft and differentiate into myeloid-lineage cells. Most commonly, the HSCs are transduced with an integrating virus that drives expression of a protein that is absent or mutated in the target disease. While this approach can achieve excellent efficacy both for disorders of the blood and other tissues (rescued through secreted transgene products), safety concerns remain due to risks imposed by insertional mutagenesis. Several instances of myelodysplastic syndromes and leukemias have arisen in clinical trials, highlighting a need for better preclinical tools for assessment of oncogenic risk. In a recent study published in Molecular Therapy, Schwarzer, et al. present one such tool, a machine-learning based assay that uses transcriptomic signatures to predict vector safety.

Thus far, one of the best approaches for predicting oncogenic risk has been the In Vitro Immortalization (IVIM) assay, in which HSCs are transduced with test vectors and plated at low density in multiple wells. At limiting densities, only immortalized cells will proliferate, and the frequency of such proliferative clones can be used to assess oncogenicity. While useful, this approach offers limited sensitivity and requires extensive technical replication due to inter-assay variability. The group’s new assay, the Surrogate Assay for Genotoxicity Assessment (SAGA), builds upon this existing framework by identifying shared transcriptomic signatures of vectors with known IVIM and clinical genotoxicity, and using these signatures as the basis for a predictive algorithm. This approach condenses the transcriptomic space into an optimal combination of 11 core predictors that are used to construct a continuous Normalized Enrichment Score (NES), which serves as a binary classifier for genotoxicity. Importantly, the SAGA NES outperforms IVIM scores as a binary classifier, with improvements in accuracy, sensitivity, and negative predictive value.

In addition to developing a tool with tangible utility, the study also sheds new light on the mechanisms of vector-mediated oncogenesis. Promoter and enhancer elements within integrating vectors have the potential to activate expression of genes proximal to the integration site, and oncogenesis can result from integration near proto-oncogenes. Here, the authors demonstrate that genotoxic vectors induce a shared, unique gene expression signature characterized by upregulation of genes for stemness, DNA-replication, and, somewhat surprisingly, myeloid differentiation. These insights add to a growing body of evidence suggesting that relatively disparate oncogenic vectors may transform HSCs through similar downstream perturbations.

In addition to enabling better safety testing of candidate vectors, SAGA could also be a useful tool in the quest for greater efficacy. For some disease indications, where modified HSCs are intended to secrete transgene products in sufficient quantity to rescue untransduced cells, efficacy improvements could be realized with stronger promoter and enhancer elements – as long as oncogenicity is not concurrently increased. When combined with screens for expression level, SAGA could facilitate the identification improved regulatory elements and vectors that yield a favorable balance of high expression and low genotoxic potential. As an instrument with such broad utility, SAGA could prove to be an incredibly valuable addition to the HSC gene therapy tool kit.

From Molecular Therapy


2020 Impact Factors 

It is our privilege to share with you the 2020 impact factors for the Society's family of journals:

 

  • Molecular Therapy: 11.454 (+27 percent)

    • Ranked 11/140 in the category of medicine, research, and experimental and 6/159 in the category of biotechnology and applied microbiology

    • Received 24,333 citations in 2020

  • Molecular Therapy-Nucleic Acids: 8.886 (+26 percent)

    • Ranked 13/140 in medicine, research, and experimental

    • Received 8,812 citations in 2020

  • Molecular Therapy-Oncolytics: 7.200 (+75 percent)

    • Ranked 20/140 in medicine, research, and experimental and 44/242 in oncology

    • Received 1,582 citations in 2020

    • Highest percent increase across more than 50 journals from publisher Cell Press

  • Molecular Therapy-Methods & Clinical Development: 6.698 (+48 percent)

    • Ranked 25/140 in medicine, research, and experimental

    • Received 3,268 citations in 2020

This month, read these new issues of Molecular Therapy family journals:
Molecular Therapy
Molecular Therapy: Methods & Clinical Development
Molecular Therapy: Oncolytics

You can still submit your papers for a special issue of Molecular Therapy: Oncolytics on combination gene and cellular immunotherapies by August 1!

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Society News


Congratulations to the #ASGCT21 Outstanding Poster Presentation Awardees

We'd like to congratulate the Oustanding Poster Presentation Award winners from the 24th Annual Meeting! Every year, the top poster presenters from each of the Annual Meeting poster sessions receive this award. Any ASGCT Member or Associate Member who submits an abstract to the Annual Meeting is eligible. You can look at the list of recipients here.

Learn About Wilson Disease with Patient Education Resources

ASGCT recently released new resources on Wilson disease, a rare genetic disorder that causes excess copper to be stored in the body. Visit our Patient Education site to watch a new video and download an infographic and resource kit. Feel free to share this information with anyone you know who may benefit!

Apply for Career Development, Diversity & Inclusion Awards

Applications are still open for two types of funded awards totalling nearly $1 million! The Career Development Awards support six members working toward independence in their gene and cell therapy careers, and in 2021 the values have doubled to $100,000 each! We also have new Diversity & Inclusion Awards that will fund two fellowships for underrepresented minorities, one opportunity for a member to research a condition disproportionately affecting minorities, and one mentorship program. Learn more about all the awards here.

Register for a Roundtable AAV Discussion August 18

Join us for a free, virtual AAV Integration Roundtable on August 18. AAV vectors are known to deliver transgenes via in vivo gene delivery to support long-term expression. While some vectors are known to be integrating, other vectors like AAV have been historically understood to result in low levels of integration. The virtual Roundtable will address this topic with presentations and discussions from experts in the field. Registration is now open our our website.

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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


Society Shares Insights on Clinical Challenges 

In June ASGCT responded to a request for information from the National Center for Advancing Translational Sciences (NCATS) on the challenges that the rapid pace of development of gene therapies places on the existing diagnostic and delivery infrastructure. To facilitate the equitable and efficient delivery of gene therapies to more patients, the Society noted its support of key policy priorities, including the following: expeditious addition of new conditions to be included in newborn screening; Medicaid coverage of genetic testing; allocation of additional funds to the Center for Biologics Evaluation and Research (CBER); and full coverage and enabling of novel payment models. ASGCT also highlighted its methods for creating resources for its Patient Education Program to facilitate timely awareness of gene therapy options for patients and their families.  

ASGCT-Endorsed Support for Research Reintroduced in Congress 

ASGCT endorsed the National Biomedical Research Act (S.2187), which was reintroduced this month by Senator Elizabeth Warren. The bill would create a new $100 billion fund to support innovative research and development through NIH and FDA initiatives, including for basic research; research on diseases with unmet medical needs or for which current treatments are limited, inadequate, or burdensome; research to improve the predictability, consistency, and efficiency of regulatory review and decision-making; post-market surveillance; and research by investigators from traditionally underrepresented groups. ASGCT has supported this bill when introduced in prior years as part of its ongoing policy priority of supporting robust funding for gene and cell therapy research.

Recent Events Focus on Equitable Gene Therapy Development

Last month, ASGCT hosted two virtual events focused on enhancing access to gene therapies through more equitable development. At the Forum on Gene Therapy for Underserved Populations on June 22, key stakeholders presented various approaches to address the challenges in developing gene therapy for people with ultra-rare diseases. The event also covered mechanisms to support increased clinical development of gene therapy for those living in countries with lower-income economies, such as through a nonprofit biotech model and through philanthropic foundation funding of research on more transportable gene therapy approaches. 

On June 29, Advancing Gene and Cell Therapies in South Africa brought together South African and U.S. speakers with experience in clinical development to share scientific and regulatory insights on developing clinical gene therapy research in South Africa. This program was part of ASGCT’s efforts to facilitate clinical development in countries with middle-income economies through collaborative education programs. The recordings of both events are available on ASGCT’s website.  

Industry News


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