Gene Therapy Progress: Challenges and Opportunities

What a whirlwind the ASGCT 2021 Annual Meeting was. If your week was anything like mine, you are still working through a number of the recorded sessions which you saved for later across a veritable sea of open browser tabs. May I humbly offer, if they are not there already, that you add two key sessions to your to-watch list:

• Toxicities and Limitations of Gene Therapy
• Viral Vector Safety: A Renewed Focus on Vector Safety and Innate Immune Responses to Leading Viral Vectors

Taken together these two sessions review a number of the recent clinical findings and emerging concerns around viral vector gene therapy and their possible underpinnings. Certainly, several events in the past year have left most of us in the field thinking critically about a number of questions around how to best establish the therapeutic window for a novel gene therapy prior to first-in-human testing.

• What are the key elements which require de-risking (e.g. capsid-related tolerability, ssDNA/dsDNA related tolerability, payload-specific tolerability, etc.)?
• What are the mechanisms of those concerns (e.g. adaptive immunity, innate immunity, complement, etc.)
• What are the limitations of de-risking these concerns in preclinical models? And further, what are the limitations of doing so in wild-type animals without the underlying disease states expected in the clinic?

But as well, these events and concerns have turned us looking forward to novel solutions as well (e.g. optimized premedication regimens, improved capsids with better transduction efficiency/product quality, improved delivery to target tissues, etc.) However, we probably have all felt that we are a bit limited in our ability to solve these problems as there is still a limited understanding of the underpinnings. That is where these two sessions come in.  Now, I’m not promising that all the questions we have in the field will be answered herein, but certainly these sessions represent a start of the conversation.

The field is growing by leaps and bounds these days, and we share a mutual responsibility to each other, and more importantly to patients, which should transcend any competitive instincts that may creep into our efforts. Sessions like the two above where we work to examine not just our successes, but also our limitations, are crucial to our efforts as we advance these therapies.  And I am grateful that ASGCT gives us an annual opportunity to review and assess the challenges ahead of us. 

Dr. Walsh Martin is a principal at Tremont Therapeutics and a member of the ASGCT Communications Committee.

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