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Optimizing Vector Delivery to Reduce Risk: Q&A With Beverly Davidson, PhD, and Misun Hwang, MD

Published on February 6, 2023 in Cornerstone Blog · Last updated 10 months 3 weeks ago
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Drs. Davidson and Hwang are collaborating to develop an alternative and innovative method for the delivery of gene therapy.

Drs. Davidson and Hwang are collaborating to develop an alternative and innovative method for the delivery of gene therapy.

Editor's Note: Supporting CHOP's vision to be the global leader in pediatric cell and gene therapy discovery and treatment is the Cell and Gene Therapy Collaborative. The CGTC aims to significantly increase the number of potential new pediatric cell and gene therapies that are the product of CHOP-led research, and to accelerate the pace of clinical development to provide new therapies to children. One way they're doing this is through the Cell and Gene Therapy Seed Grant program, which is designed to promote early-stage development of new ideas in either the engineered cell therapy or gene therapy space — with the goal of achieving preclinical proof of concept by the end of the grant period.

In this three-part Q&A Cornerstone series, we're highlighting the 2023 recipients of this mentoring grant. Today's posting features the gene therapy delivery research and partnership of Beverly Davidson, PhD, Chief Scientific Strategy Officer at CHOP, and Misun Hwang, MD, Director of the Section of Neonatal Imaging and an attending radiologist at CHOP.

Can you describe the gene therapy project you're working on and the context for its development?

Dr. Davidson: Our seed grant explores the possibility of using Dr. Hwang's cutting-edge delivery approach to encapsulate the vectors that we deliver to tissues to see if we can improve the focal targeting of gene therapy in the brain without doing an entire surgical intervention. Right now, we either go through the blood or through a surgical intervention to infuse particular regions; if we can control where the therapy goes through a vascular delivery with Dr. Hwang's ultrasound approach, we put the best of the two properties together.

Dr. Hwang: Dr. Davidson's group has done a tremendous job of advancing gene therapy to pediatric patients with central nervous system diseases. But I think one of the more practical challenges affecting the field overall is the targeted approach of these intravascularly or intracisternally injected adeno-associated viruses (AAV). Targeting these gene-carrying vectors to specific brain regions is challenging because they can go throughout the body and result in associated systemic toxicity. Despite all the advances in the field, we think that there must be an approach to deliver AAV in a safe manner and that can be implemented more easily.

Though this is still in the evolution phase, we are testing the feasibility of combining focused ultrasound with intravascular delivery to see whether we can enhance the targeted delivery of therapies while reducing the systemically injected concentration and systemic toxicity. By using a low-intensity, focused ultrasound together with intravenously injected microbubbles, we are able to open the blood-brain barrier in a controlled manner and direct these vectors to the brain region of our choice — whether it's a local region or multiple ones. Moreover, a higher concentration of these antiviral vectors can enter those regions.

How will your seed grant project drive cell and gene therapy science and/or therapeutics forward?

Dr. Hwang: Our eventual goal is to bring this gene therapy delivery method to children with incurable brain disorders who need to receive life-saving care but face high risks and toxicities. We're trying to reduce the risks and provide an alternate, less invasive method of care..

Dr. Davidson: There is not a one-size-fits-all for gene therapy. While we can't discount the success of the gene therapy solutions in treating children with spinal muscular atrophy, trying to scale that approach to additional childhood-onset neurodevelopmental diseases made it obvious that it's not uniformly applicable. Many of us in the CGTC are trying to develop additional methods that are appropriate for different kinds of patients. We want to take the best virus for the patient but apply a different delivery method — that is the focus in this project.

After the completion of this grant, what do you see as next steps?

Dr. Davidson: We would love to see this work advance and continue. This seed grant will help us get the preliminary data to look for additional sources of funding.

Why do you think the pairing of scientists is important, and how does this type of collaboration enhance your team's work?

Dr. Davidson: What's unique is the marriage of two scientists with very different skill sets where each taking independent approaches to the problem and summing them together is greater than the parts.

How does the culture, mission, and capabilities of CHOP's Research Institute foster collaborative cell and gene therapy projects such as yours?

Dr. Hwang: CHOP fosters multidisciplinary collaboration through many platforms, and this is just one of them. Scientists from different disciplines come together and create teams that can lead to higher-impact transformative care for children. I think that's a lot of what CHOP is known for.

Dr. Davidson: From my perspective, the breadth and depth of research at CHOP makes for exciting, interesting new collaborations. I think that it's not just the culture, but also the commitment to fostering new science and fostering new collaborations between physicians and scientists, that is unique.