Complex Neurological Disorders Lie on the Horizon of Gene Therapy Research

Deborah Phippard, PhD

Early research in gene therapy has largely focused on single-mutation genetic disorders, as these are the simplest and most straightforward to tackle for the modality. Looking ahead, however, these treatments have provided a proof-of-concept that may allow for the expansion of gene therapy into more complex, less well-understood neurological disorders like Alzheimer disease (AD) and Parkinson disease (PD).

CGTLive™ spoke with Deborah Phippard, PhD, the chief scientific officer of Precision for Medicine, a clinical research services organization that works with companies developing gene therapies, about the future of gene therapy research and the innovations that she is most excited about. She emphasized her hope that gene therapy may eventually provide novel treatments for complex neurological disorders that affect large patient populations and noted several promising innovations such as using artificial intelligence (AI) tools to design capsids that can more effectively deliver such treatments.

CGTLive: Where do you think gene therapy holds the most potential?

Deborah Phippard, PhD: That depends how you think about potential. Single point mutations, I think are the easiest; the lowest hanging fruit. I think they are fantastic for proof-of-concept and really allow the field to expand and think about better vector design, better clinical studies, and better transfer. I feel though that the real promise is in the big, unmet medical needs; things such as PD and AD. They're getting more and more prevalent for various reasons, which is a whole other hour long subject that we could talk about; about why we see these types of disorders increasing almost exponentially when you look at the data. So, to me the promise is those really big disorders that hit patients later in life. There are all sorts of different issues: How do you treat adults? At what point do you intervene? Has too much damage occurred? Can you bring it back? We don't have great diagnostic tools for things like AD and PD. Certainly, in my career, I always think about how if you can intervene earlier, it is a lot easier to change the course of the disease than when you have very severe symptoms. So, if you already have a significant movement disorder with something like Parkinson disease, to my mind, that is a lot harder to treat.

To think about all the things you could do with gene therapy, really, it isn't just the gene therapy field that has to expand. The whole translational field around biomarkers, diagnosis, how to intervene with patients, and even just to think about how to measure efficacy—we have some really blunt tools to determine memory deficits in AD. If we can image, the data gets a lot better, but how accessible is that going to be in a broad population, when you look at the millions of people that are going to be affected?

I feel like there's so much we can do, but we're going to have to do a lot of proof of concept. Everyone's well aware that AD and PD trials have often been very disappointing with small molecules and even with some of the biological treatments we have now, so gene therapy is poised to be useful. I think it's also a very scary topic. When you talk to people in general about gene therapy, that can be a truly terrifying thought. People are much more comfortable with swallowing a pill or even injecting a biologic. The thought of modulating your nucleic material—just the perception of that I think will be challenging. The flip side of that coin is that people with AD and their families, I think, are really desperate for therapy. So again, it's a very rich, promising field. I don't know that I'm going to see it come to fruition during my career, but hopefully before I'm dead! That will be nice.

Which therapies or programs currently in development are you most excited about?

The whole field of gene therapy is super exciting to me. I talk to one company and think “Oh, that's so cool!” and then I’ll talk to another company and think "Wow, that idea is really cool as well!” So, there's really an explosion of good ideas. Something that I find particularly exciting, because it pulls different things together, is how some companies are using the latest AI tools to accelerate their discovery. There are some biotech companies out there that are using AI tools to model the viral space and design a capsid that would have the tropism to go to the cells of interest. Of course, once you have the design, you have to go test it at the bench, but I think being able to use new tools like AI is really going to explode the field with what we can and can't do. Delivery is one of the biggest problems we have for gene therapy in the central nervous system. How do we get through the blood-brain barrier? How do we get to the right cells? If we can harness the new AI tools to really address that question, I find that really exciting.

Is there anything else you want to share with the audience?

There is so much we can do with our toolbox. I think the biggest thing to me is that when it's this exciting you have to ask how you move forward without another shoe dropping. In the history of gene therapy, we've had the occasional very bad outcome. Probably everybody can quote things that happened back in the early 2000s. I really hope that we are cautious with how we're moving forward, but still being very innovative. This field has so much promise; I would hate to see something get shut down in the way gene therapy got semi-derailed in the past because of a few very serious adverse events.

I really hope we go full speed ahead, but we still have that caution that we keep the patients in mind, and we really think of innovative ways to go there. There is so much promise in this field and I'm very glad that at this point in my career I can be part of bringing these drugs to patients. We really are in the part of medicine where a lot of our patients literally did not have any hope of a good life or even a normal life before gene therapy. I'm very excited to be part of this and I'm sure everybody listening feels similarly.

Transcript edited for clarity.