Directed Evolution Holds Potential to Improve AAV Vector-Based Gene Therapy

Barry J Byrne, MD, PhD
Credit: MDA

This is the third part of an interview with Barry J Byrne, MD, PhD. For the second part, click here.

Adeno-associated virus (AAV) vector-based approaches to gene therapy constitute a substantial portion of gene therapy products currently approved by the FDA as well as of gene therapy products currently in clinical and preclinical development. Because this approach comes with several key drawbacks, some investigators and companies are making the shift to other viral and nonviral methods of gene therapy delivery. On the other hand, some are seeking to improve the AAV vector-based approach through the use of strategies like using directed evolution to produce novel AAV capsids that possess specific qualities. For example, directed evolution may be used to produce capsids that have greater tropism for a particular organ of interest than other available capsids.

As part of a larger discussion about the upcoming MDA Clinical & Scientific Conference, which will be held on March 3-6, 2024, in Orlando, Florida, CGTLive™ spoke with Barry J Byrne, MD, PhD, the chief medical advisor of Muscular Dystrophy Association (MDA) and a physician-scientist at the University of Florida, about his views on the future of gene therapy in general. He focused on the potential of directed evolution to improve AAV vector-based approaches to gene therapy for neuromuscular disease and expressed general optimism about future innovations in the field.

CGTLive: Can you speak about what you see for the future of gene therapy in general? Is there anything specific you are expecting to happen next or believe will be a focus of development?

Barry J Byrne, MD, PhD: As gene therapy has evolved using known AAV vectors that have some evidence for specific tropism to muscle, several investigators and early-stage companies have developed ways to evolve gene therapy vectors through something known as directed evolution. These directed evolution efforts are able to identify AAV capsids that bind to new ligands that are specifically represented in muscles. These are known as myotropic AAVs and the myotropic AAVs are really probably the next frontier to improve targeting both to skeletal and cardiac muscle (often affected by neuromuscular diseases) as well as potentially stem cells, which are really ultimately the target of a transformative, lifelong therapy for gene editing. [From] the ability to do directed evolution using AAV vectors based on the structure of AAV that was originally determined in 2012 this field has really accelerated in the last few years and I'm particularly hopeful that we'll continue to find new ways to manufacture these products at lower costs, improve the efficiency of delivery, and lower doses for the purpose of easily accessible therapies that are going to have an even greater impact in the future.

This transcript has been edited for clarity.

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