EP 226: Scaling AAV gene therapy with David Dismuke of Forge Biologics & Steven Gray of UTSW

Value of the Information & Strength of the Argument

The value of the information is high, as it provides an insider perspective on AAV manufacturing and CNS gene therapy from two experts with decades of combined experience. The discussion is practical and addresses real-world challenges, such as the trade-offs between full and empty capsids, the impact of vector design on manufacturability, and the cost curve of gene therapy. The argumentation is solid, grounded in their direct experience, and they provide concrete examples, such as the improvement in production yields from E12-E13 to mid-E15 VG/L. They also draw useful analogies to the monoclonal antibody industry to illustrate potential cost reductions. However, some claims are general and lack specific data or citations, and the discussion is more conversational than rigorously structured.

Scientific Rigor, Source Quality, Title Accuracy

The scientific rigor is moderate: the speakers are credible experts, but they do not cite specific studies or data. The quality of sources is limited to their own experience and the mention of Forge Biologics’ work. The title accurately reflects the content, focusing on scaling AAV gene therapy with the two named experts. The discussion is coherent and stays on topic, though it could benefit from more references to published research or clinical trial outcomes.

The title accurately reflects the content, focusing on scaling AAV gene therapy with the two named experts.

8/10

High-level experts with direct industrial and academic experience in AAV manufacturing and CNS gene therapy. The discussion is grounded in practical knowledge, but lacks detailed citations or data. Some claims are general and not fully substantiated.

• 00:00Intro to The Genetics Podcast
• 00:59Welcome to David and Steven
• 01:47David and Steven’s overlapping academic paths and long-term collaboration
• 03:56Steven’s research on AAV engineering for central nervous system (CNS) gene therapy
• 05:15Forge Biologics’ platform approach to scalable AAV manufacturing
• 07:07How AAV vectors are manufactured
• 09:12How CNS AAV vectors are designed, tested, and refined across programs
• 11:57How manufacturing quality and trial outcomes can shape AAV development decisions
• 16:37Factors that impact the ratio of full versus empty AAV capsids
• 18:58Manufacturing scale, capsid efficiency, and the future cost curve of AAV gene therapy
• 26:32Scaling AAV manufacturing for common diseases and the shift toward industrialized production models
• 29:28Engineered AAV capsids for CNS delivery and the tradeoffs between innovation and platform stability
• 33:09Next-generation AAV delivery and gene editing technologies
• 37:07Lessons from Jude Samulski on translating AAV science into real-world therapies
• 40:38Closing remarks

• Forge Biologics — Mentioned as the company where David Dismuke is CTO, and as a CDMO for AAV manufacturing.

• Forge Biologics — The company's website provides information on their AAV manufacturing platform and services, supporting the discussion.