Gene Therapy Pioneer Kathy High On Balancing Risk vs. Benefit In AAV-Vector Gene Therapy Development

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

As I wrote in a past blog post, when one of the pioneers of gene therapy speaks, it’s probably worth dropping everything to listen. That’s how I found myself pushing aside my (alarmingly large) pile of writing projects to attend a recent STAT+Conversation with Kathy High on the future of gene therapy. If you want to read a full transcript of the conversation or listen to the discussion, it is available to STAT+ subscribers; it’s great to hear her personal experiences throughout her tenure in the gene therapy world. But what struck me most throughout the conversation was High’s careful attention to the tricky risk/benefit equation with which the cell and gene therapy industry is grappling today — especially as it relates to the nascent regulatory pathway.  

On one hand, of course, there’s the question of the clinical/safety risk vs. benefit ratio regulators must weigh as they make the (sometimes controversial) decisions about which treatments are approved — and when. As High explained:

When regulators make decisions about a drug approval, they have to carefully consider the amount of safety data and the critical quality attributes that inform the performance of a new product. For some diseases, like hemophilia, for example, we have a long history of safety data for established treatments. As such, the risk-benefit calculation for a gene therapy approval in this indication would be different than in another disease state that has no currently approved treatments or is marked by significant nonadherence given an overly complex medical regimen. 

On the other hand, we can also see this concept carried over into the development/manufacturing side of things. Frustration at the pace of R&D, scientific advancements, and regulatory acceptance is inherent in the pharma industry, regardless of the target/therapeutic. But in the cell and gene space, in particular, the reliance upon the current generation of AAV vector — which dates back to the early 2000s — comes with a healthy amount of manufacturing challenges. In fact, a question that’s been asked at a number of conferences — and, indeed, during this conversation with High — is whether the current generation of viral vectors is holding the gene therapy field back.   

High wasn’t quick to jump to such conclusions. As she admitted, yes, there is a lot of work yet to be done to improve the delivery, manufacturability, and therapeutic applicability of AAV vectors (some efforts of which I unpack here). In fact, she sees “great synergy” emerging between protein engineering and gene therapy. She anticipates more collaboration with protein engineers could lead to the development of truncated (but still functional!) proteins, and, in turn, greater AAV-packaging efficiency.  

‘I’m not sure we could take this approach across the board, though we’ve already seen success with people doing this today,’ she added, pointing to the more straightforward example of Factor VIII, which comprises a functional truncated version of the Factor VIII gene. ‘To me, it’s a really interesting area where advances in protein design are fusing with gene therapy to lead to better outcomes.’ 

But despite the work that remains to be done, she also remains quite down to earth about the continued emphasis on the current generation of AAV vectors, adding: “Just because something is old doesn’t mean it’s not good.” (As a hematologist, she called out the important therapeutic role much older drugs like coumadin still play today).  

There’s also a benefit that can come from working with an existing technology, despite its current limitations: regulatory familiarity. Building the regulatory infrastructure for new classes of therapeutics is no mean or efficient feat. Though you likely wouldn’t find anyone to disagree with that statement, you’d probably find there are (a comedically vast) multitude of expectations across the industry over what is a reasonable amount of time for a regulatory pathway to come together. High added,  

I think sometimes people underestimate the amount of time it takes to build the regulatory infrastructure for a new class of therapeutics. One of the advantages of AAV is that we have been doing clinical investigations with AAV for more than 20 years now. So many of the challenges in clinical applications of AAV have been identified and solutions have been devised to enable the regulators to assess the safety, risk, and benefit. 

Now, I know she’s not referring specifically to manufacturing in the above quote; in fact, the number of CRLs today clearly reveals that we’re entering a period of great “regulatory chiseling” as companies and regulators further define what the CMC regulatory requirements must be for cell and gene therapies to be deemed well characterized, safe, and high quality.  

But I daresay her quote still has some significance for those of you planning your manufacturing strategies. In this day and age of buzzy innovation, next-gen vectors, new “state of the art” facilities, technologies, and capabilities, genome editing, and novel delivery strategies, the “familiar” certainly has its own fair share of benefits and opportunities.