Episode 114: Gene-Based Therapies for Parkinson’s Disease

Dan Keller 0:02

Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller, at the Parkinson's Foundation. We want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research—the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow.

Most people with Parkinson's disease begin treatment with levodopa, but in the future, treatments could potentially be delivered directly into the brain using either cell-based or gene-based therapies. In our previous episode with Professor Roger Barker of Cambridge University in England, he discussed cell-based therapy. Here, he continues the discussion with gene-based therapy: what it is, how it is envisioned to be done, what symptoms it may alleviate, and the current state of the research.

To set the stage, I first asked him what gene-based therapy actually means.

Prof. Roger Barker 1:26

Gene-based therapy is an approach where researchers essentially engineer a specific gene and inject it directly into the brain. That gene will then enter and alter cells in the local area where it has been delivered.

In Parkinson's disease, this research has generally taken one of two routes. The first is to inject a gene that codes for a growth factor designed to support dopamine cells and dopamine fibers—acting, if you like, as a sort of dopamine nerve cell fertilizer. The second approach is to inject a gene that contains the specific enzymes allowing cells to manufacture dopamine from its basic biological ingredients; this is essentially providing a recipe for making dopamine. Once injected, that code is taken up by local cells, enabling them to produce dopamine independently.

So, those are the two primary paths people have taken with gene therapy: a fertilizer to help surviving dopamine cells grow and survive better, or a genetic tool to convert existing non-dopamine cells into dopamine-producing cells.

Dan Keller 2:27

Is dopamine the only neurotransmitter that researchers are focusing on in Parkinson's disease in terms of gene therapy?

Prof. Roger Barker 2:36

It is the main one, though people have explored other pathways. There was a gene therapy trial conducted a number of years ago that targeted a structure deep in the brain called the subthalamic nucleus. Researchers tried to convert a specific group of overactive, excitable cells that produce positive signals into inhibitory, negative cells by altering the neurotransmitter contained within them.

You could think of that approach as the gene therapy equivalent of deep brain stimulation (DBS). The results were interesting, though as is often the case with early experimental trials, it was never entirely clear whether there was a definitive clinical effect. However, that remains the only major trial I know of that sought to target a neurotransmitter other than dopamine.

Dan Keller 3:20

Was that the trial focusing on glutamic acid decarboxylase?

Prof. Roger Barker 3:25

Exactly. That was the GAD trial.

Dan Keller 3:28

How exactly are these genes introduced into the brain?

Prof. Roger Barker 3:31

At the moment, the delivery method is virtually identical to cell-based therapies. If you want to target these therapies effectively, they must be injected directly into the brain. This requirement is one of the distinct disadvantages of current gene-based approaches, a challenge that also applies to cell transplantation and deep brain stimulation.

The genes must be delivered precisely to the site where you want them to operate. The surgical team maps the exact target area using brain imaging, and then a neurosurgeon infuses the therapy into that part of the brain. While neurosurgery understandably causes a lot of anxiety for patients, this is considered a relatively straightforward stereotactic operation in the surgical world. The target is a comparatively large volume, and neurosurgeons routinely perform similar, highly precise procedures every day—such as targeting and biopsying deep brain abnormalities or tumors. This procedure is essentially the reverse of a biopsy; instead of taking a tissue sample away, the surgeon is carefully infusing a therapeutic agent where it can work optimally.

Dan Keller 4:28

Are there also discussions around temporarily opening the blood-brain barrier to administer gene therapy intravenously, allowing it to cross over from the bloodstream?

Prof. Roger Barker 4:38

Yes, researchers have thought about that a great deal. It is an excellent question. If you could administer the treatment systemically—injecting it into a standard vein—and then safely open the blood-brain barrier at the exact site where you want it to enter, that would be a very elegant solution. The blood-brain barrier normally serves as a strict filter preventing circulating molecules in the blood from entering brain tissue.

People are evaluating various techniques, such as focused ultrasound, to temporarily open this barrier. However, that technology is still very much in its infancy. There are three primary hurdles to overcome: first, the duration for which you can safely open the blood-brain barrier to allow a sufficient dose to cross; second, determining how far the therapeutic genes will actually diffuse through the targeted brain tissue once they cross over; and third, the safety implications of systemic administration. If you inject a gene therapy into the general bloodstream, it travels throughout the entire body, meaning you must meticulously evaluate where else it might bind and whether it causes adverse side effects in other organs.

Dan Keller 5:31

Would this sort of therapy mainly address motor symptoms, or could it impact other symptoms as well?

Prof. Roger Barker 5:37

Outside of the GAD trial we discussed, the primary gene therapy approaches are predicated on the exact same principle as dopamine cell transplantation: rescuing or restoring the dopaminergic system. Consequently, they exclusively target the dopamine-responsive elements of Parkinson's disease, which are predominantly motor-driven.

There are certain cognitive and executive thinking problems that tie directly to dopamine disruptions within the basal ganglia—the structures located deep within the brain's core. Restoring dopamine levels in the striatum will primarily alleviate motor deficits. While patients might experience subtle cognitive benefits, the improvement will be most apparent in reducing the stiffness, rigidity, and slowness of movement—or bradykinesia—that characterize the disease.

It is also important to note that these therapies, as currently designed, are not strictly disease-modifying in a global sense. You could argue that introducing a growth-factor fertilizer slows down the localized loss of remaining dopamine neurons, which represents a form of disease modification. However, it is highly unlikely that this alone would halt or undo the broader, systemic disease process, which would eventually overwhelm the local benefits of a growth factor.

Dan Keller 6:45

Where do these trials and experiments stand right now, particularly in comparison to cell-based therapies?

Prof. Roger Barker 6:52

They are at a very comparable stage of clinical development. If you look back at the modern timeline, cell-based therapies originally began in the late 1980s and dominated research throughout the 1990s. They eventually fell out of favor due to a lack of clear efficacy in larger, double-blind trials, as well as the emergence of side effects like graft-induced dyskinesias.

In the early part of this century, gene therapy gained significant momentum and has been highly in vogue for the last 10 to 15 years. This includes both growth-factor approaches—using a factor called neurturin to preserve dopamine cells—and direct dopamine-replacement strategies. Two biotech companies in particular, Voyager Therapeutics and Oxford Biomedica, have been actively developing these platforms.

Their progress runs completely parallel to the cell therapy field, which has itself re-emerged into a new phase using advanced stem-cell-derived dopamine neurons rather than the older, fetal tissue sources. Both fields are concurrently running modern clinical trials, and it will be fascinating to see whether one approach eventually dominates, given that they are both ultimately trying to repair the exact same issue: the loss of dopamine fibers and innervation in the brain.

Dan Keller 8:16

Looking ahead, without setting an exact timeline, what do you see for the ultimate future of both cell-based and gene therapies?

Prof. Roger Barker 8:26

We are at a truly critical juncture. To advance further, these next-generation therapies must demonstrate a marked, undeniable clinical benefit, which hasn't quite been achieved yet because these newer versions haven't been evaluated in long-term human trials for long enough. We need to see consistent, robust efficacy. The historical issue with fetal dopamine cells was their extreme inconsistency from patient to patient, while early gene therapy trials simply did not produce a large enough therapeutic signal to be competitive with standard care.

We have to wait and see if they can truly compete with existing treatments in terms of effect size and predictability. Tied directly to that is the issue of manufacturing costs; these are highly complex, bespoke biological therapies that are expensive to produce, so global affordability will be a major discussion point.

Ultimately, however, if they prove to be affordable and deliver an effect equivalent to what we achieve with deep brain stimulation or oral medications, you could see them competing as early-line interventions. In an ideal future vision, a patient would present with an early diagnosis of Parkinson's, respond well to a temporary test dose of levodopa, and then immediately receive a one-off gene or cell-based therapy. If administered early enough, it could completely eliminate the need for daily oral medications during those initial years. Eventually, as the disease inevitably progresses, non-dopaminergic, non-motor symptoms would become more prominent and require separate management, but this strategy could completely revolutionize how we manage early-stage Parkinson's. Everything we currently do in standard clinical practice revolves around chronically replacing dopamine via daily pill regimens.

Dan Keller 10:12

What are the key watchwords or cautions for individuals who are considering joining a gene or cell-based trial, or who are looking at commercial options marketed as therapies today?

Prof. Roger Barker 10:22

Patients and families must exercise a great deal of caution. Generally speaking, gene therapy trials carry an inherent layer of safety regarding how they are organized. Developing a viable gene therapy requires immense capital investment and highly specialized scientific infrastructure. Consequently, these programs are almost exclusively tied to reputable biotechnology companies or major academic institutions running formalized, rigorously monitored clinical trials. It would be exceedingly difficult to stumble into a gene therapy protocol that wasn't fully vetted, structurally funded, and easy to verify through official regulatory channels.

The cell transplantation landscape, however, is completely different and requires extreme vigilance. There is a widespread industry of "stem cell tourism," where private commercial clinics around the globe aggressively market unproven, unregulated therapies. They often rely heavily on anecdotal patient testimonials rather than peer-reviewed data, and they utilize poorly defined cell mixtures that they claim can cure a wide host of unrelated conditions, with Parkinson's simply tacked onto the list.

I would be incredibly wary of any clinic making these claims, particularly if you are required to pay out-of-pocket. There is absolutely no ethical or scientific reason a patient should pay to receive an experimental, unproven therapy. Furthermore, it is important to remember that as of today, there are no proven, licensed disease-modifying therapies for Parkinson's disease. While many alternative treatments are advertised as being able to halt or cure the disease, those claims are entirely unproven. Anyone claiming they have a verified cure or a therapy proven to slow down the progression of Parkinson's should be viewed with extreme skepticism.

Dan Keller 11:49

I suppose it is also worth emphasizing that nothing in this space is officially regulatory-approved at this point; everything remains strictly experimental.

Prof. Roger Barker 11:56

It absolutely is. Patients understandably worry that they are missing out on an available breakthrough or wonder if a therapy has already been proven elsewhere in the world without their knowledge, but you are entirely correct: this is strictly the experimental phase.

Every well-designed trial, even those that do not meet their primary endpoints, teaches us invaluable lessons about how to safely proceed. Most scientific breakthroughs fail on their very first human attempts. The most critical component of clinical research is that we learn as we go, systematically incorporating that knowledge into the design of subsequent trials until we ultimately arrive at a proven, highly effective therapy that can be formally licensed for widespread clinical use.

Dan Keller 12:33

Very well said. I appreciate your time and perspective. Thank you very much.

You can find more information on the topics of gene-based and cell-based therapies by visiting parkinson.org and searching for "Roger Barker." There, you will find an expert briefing he presented, as well as our previous podcast episode in which he detailed cell-based therapies.

As Professor Barker strongly advised, one must be exceptionally cautious when considering entering a cell-based clinical trial, as there are many unethical claims being generalized about such studies, with some commercial entities inappropriately promoting them as standard treatments. Fortunately, the Parkinson's Foundation has an excellent article available in those search results titled Stem Cell Therapies for Parkinson's: 5 Questions to Ask Before Participating in a Clinical Trial.

If you have any questions about today's topic, or any other aspect of living with Parkinson's disease, our compassionate information specialists are available to provide answers in both English and Spanish. You can reach the Parkinson's Foundation Helpline directly at 1-800-4PD-INFO. News, educational event updates, and research resources are always available by joining our email list at the bottom of our website's homepage.

If you would like to leave feedback regarding this podcast or any other subject, please do so at parkinson.org/feedback. If you enjoyed this episode, please be sure to subscribe, rate, and review the series on Apple Podcasts or wherever you access your favorite podcasts.

At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life today. To that end, we will continue bringing you a new episode in this podcast series every two weeks. Until next time, for additional information and resources, please visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO, which is 1-800-473-4636. Thank you for listening.

Roger Barker, BA, MBBS, MRCP, PhD is the Professor of Clinical Neuroscience at the University of Cambridge and Consultant Neurologist at the Addenbrooke’s Hospital Cambridge. He is a PI in the MRC-Wellcome Stem Cell Institute in Cambridge and Director of the MRC funded UKRMP Stem and Engineered cell hub.

His research seeks to better define the clinical heterogeneity of two common neurodegenerative disorders of the CNS- namely Parkinson’s (PD) and Huntington’s disease (HD). This has helped him define the best way by which to take new therapies into the clinic including novel experimental therapeutics such as cell and gene therapies.