Episode 169: Implications of 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, gene-based therapy is among the list of treatment options currently being investigated for its potential use in Parkinson's. It involves inserting genetic material into the brain to impact symptoms. Broadly, genetic material consists of DNA or RNA, which direct the creation of proteins. The usual approach has been to fix a piece of damaged DNA or to replace a non-working gene, but newer ideas are exploring the ability to silence or turn off excessive copies of a gene, or to make substances that encourage new cell growth. This also has the potential to enhance the effectiveness of drugs in alleviating symptoms. I spoke with Dr. Andrew Fagan of New York University Langone Health to find out how gene therapies may be applied to Parkinson's disease. What I found out was that ideas about gene therapy have now gone beyond just making more dopamine and may even apply to treating the underlying causes of Parkinson's. Before we begin, a few basic concepts: genes are contained in DNA, which is the ultimate blueprint or code for everything a cell makes or does, from DNA, a copy is made, which is messenger RNA, called mRNA for short. This message is sent to some machinery in the cell, instructing it how to make proteins. Dr. Feigin sets the stage for how different forms of genetic therapy may eventually be applied to Parkinson's disease.

Dr. Andrew Feigin 2:26 Gene therapy is use or manipulation of genetic material, and genetic material can refer to either DNA or RNA to treat or prevent disease. In this case, Parkinson's disease. I would actually say that the definition has changed over the years. I think originally many people would have defined gene therapy as a therapy that adds a new gene or replaces or repairs a mutated gene to treat a disease, but actually now there are a wider array of tools within gene therapy, and some of which are don't involve the use of genetic material, actually, but are in fact drugs that can alter the production of genes. So, I think this broader definition of the use or manipulation of genetic material. The other thing, by the way, is genes are made up of DNA, so when you think of gene therapy, would kind of imply that you're talking about therapy aimed at DNA, but in fact I think it's more useful to speak of it as genetic material and include RNA, which is a kind of a code that comes from DNA that produces a protein.

Dan Keller 3:33 Good, we can get into that a little bit more after a little bit of setting the stage here. Briefly, what is the difference between gene therapy and cell-based therapy.

Dr. Andrew Feigin 3:44 Gene therapies, as I mentioned, are targeting genes or introducing genes that will then make proteins that alter the symptoms of Parkinson's disease. So, it doesn't involve actual cells, it involves genetic material, and whereas cell-based therapies involves, as the name implies, the use of cells, often what are referred to as stem cells, or other kinds of cells to treat Parkinson's disease, and in fact doesn't involve the manipulation of genetic material,

Dan Keller 4:17 as you had said, genes are DNA, and they eventually code for making proteins, but dopamine is not a protein. So, how does gene therapy possibly lead to enhancing dopamine?

Dr. Andrew Feigin 4:33 That's a complicated question, and there are many different approaches. In the simplest way, just to answer your exact question about affecting dopamine, is that you can introduce genes, and there have been approaches like this in people with Parkinson's disease that change the way levodopa is converted into dopamine and make kind of the process more efficient, so there's an enzyme called AADC, or aromatic amino acid decarboxyla, sometimes referred to as dope. Decarboxylase, and that enzyme is one of the enzymes responsible for converting levodopa, which is the drug, into dopamine. It turns out that that enzyme is deficient in people with Parkinson's disease. Actually, so you could potentially take that gene, introduce it into the part of the brain where you want more dopamine, and make the conversion of levodopa into dopamine more efficient, so that would be one form of gene therapy, and there are several approaches that have been in human trials trying to do just that, to introduce the gene for AADC into the part of the brain where most of the dopamine is made, called the putamen, so that more AADC is made, and it makes the process of converting levodopa into dopamine more efficient and more robust, and then there are other enzymes. I simplified it a little bit, and so there's been some other approaches about introducing multiple genes that help to do that. So that's kind of the simplest answer to your question, I think. Maybe on a deeper level it's possible to think about treating Parkinson's disease in a way where you're modifying the disease, so in other words, if somebody has Parkinson's disease and is losing these dopamine cells, as you said, but still has some, if you could alter the way those cells are lost over time and prevent them from being lost by introducing or affecting genes that seem to be contributing to the progression of the disease, you could sustain or make what dopamine cells are still there last longer using gene therapy, and then maybe even better is that you potentially could use gene therapy to make dopamine cells grow back, and that's an approach that's also been used and been tried in patients with Parkinson's disease, so not only are you maintaining what dopamine cells people have, but actually causing the growth of more dopamine connections in the brain using what are genes for what are called neurotrophic factors, or brain growth factors. Well, there's one in particular that we think might have relevance to Parkinson's disease, called glial-derived neurotrophic factor, or GDNF. So that idea behind that form of gene therapy, introducing the gene that drives the production of a neurotrophic factor like GDNF and increases the amount of GDNF in the part of the brain that seems to be losing dopamine cells, could stimulate the production of more dopamine terminals, more dopamine connections, and thereby treat the disease,

Dan Keller 7:22 so in that case, would the gene therapy be aimed at increasing more glial-derived neurotrophic factor, which would stimulate dopamine-producing cells?

Dr. Andrew Feigin 7:34 That's exactly the idea. You know, once you start thinking about these issues, you realize there's a lot of ways in which gene therapy could have a role in trying to improve, specifically in answering your question, dopamine production beyond just raising levodopa or raising dopamine levels, put it that way.

Dan Keller 7:52 How far along are these approaches, and which ones have shown some promise at this point?

Dr. Andrew Feigin 7:57 That's a good question. I would say gene therapies have been tried in people with Parkinson's disease for the past something like 15 years, and various different approaches. I think maybe one of the first approaches was a study that I was actually involved in that used gene for a protein called GAD, or glutamic acid decarboxylase. That was one of the first ones, I think we actually started that trial in 2007 something like that. The idea here was that the gene would produce a brain chemical called GABA in a part of the brain called the subthalamic nucleus, and I want to get into too many technical details here, but the idea was that if you could produce this inhibitory neurotransmitter in a part of the brain where we normally, for example, one of the therapies that exist for advanced Parkinson's disease is deep brain stimulation, where an electrode is put into the subthalamic nucleus. This would be kind of an equivalent of a chemical version of that. You put in a gene for an inhibitory neurotransmitter that would kind of quiet the activity of the subthalamic nucleus, and that therapy actually, I think, did show some promise, and there were multiple publications, and is actually now 15 years later has been picked up and is being pursued again. So that's just one example. It's hard to answer your question about where things stand without talking about specific therapies, because some, some have made more progress than others. But with regard to the neurotrophic factor, that's been tried actually numerous times in several studies for Parkinson's disease, something called nurturin, which is a form of GDNF, glial-derived neurotrophic factor, that we talked about, has been tried in several clinical trials, and I would say seems to be safe and well tolerated. That first of all, that's probably the most important thing. Obviously, we want these drug therapies to work, and there is some indication that there could be some benefit to these therapies is far from being proven, I would say, but does seem to be safe and well tolerated, and there are technical issues about how these things are delivered that can affect the efficacy, how well they work to improve the signs and symptoms of Parkinson's disease, and so many of these approaches with the neurotrophic factors now are working more. The technology of how to cover the region of the brain that we think is important surgically, because these are therapies that have to be delivered surgically into part of the brain. How to get good coverage of the region that you want covered, and to get good production of the protein that you're trying to increase. And so the details of how you deliver these therapies, there have been advances. I think we haven't heard the end of the story, with, for example, something like the neurotrophic factors, and same goes for the enzymes that improve the efficiency for how dopamine is produced from levodopa. So, I think all of these things are in transition, are still being developed, have entered human trials with some, I don't know if I'd say setbacks, but with some, you know, results that were, I think, hopeful, but didn't prove that they're beneficial. But I think, as the technology improves, as we learn more, these therapies are being pursued further. Put it that way, by the way, I haven't talked about all the potential ways that gene therapy could be used for affecting, in a positive way, Parkinson's disease, but those are some of the ones that have been in human trials,

Dan Keller 11:03 for the ones that you discussed, are they mainly aimed at motor symptoms? Would they have any effect on the non-motor symptoms, autonomic things, constipation, balance, even temperature regulation, whatever?

Dr. Andrew Feigin 11:19 Yeah, that's an excellent question. So, I think the therapies that, in general, are targeting dopamine and trying to raise dopamine levels likely would not have an impact on the non-motor features of the disease that you mentioned, but that's a kind of, I think, to some extent a simplification, because, for example, if you could make the production of dopamine within the motor part of the basal ganglia, more efficient, so you might make it so that somebody needs less levodopa as the therapy. You might improve some of the non-motor features by being able to give less levodopa, which can cause side effects. Non-motor types of side effects, for example, levodopa can worsen constipation, and levodopa can worsen drops in blood pressure, what's called orthostatic hypotension. So, if you could lower the level of levodopa and still get good production of dopamine within the motor circuit, you might be in that, in kind of indirect way, be able to improve some of the non-motor features.

Dan Keller 12:18 What are some caveats or cautions for people who would be looking at a trial of gene-based therapy, possibly volunteering for it.

Dr. Andrew Feigin 12:29 One of the things you should go in with your eyes wide open, I guess, is that for most gene therapies for Parkinson's disease, we're talking, at least the ones that have made it into human trials, we're talking about therapies that require, as I mentioned, a neurosurgical procedure, so I think most of the technology for the neurosurgical procedures is pretty well established now, since we, you know, have an FDA-approved treatment of Parkinson's disease that requires a neurosurgical procedure, DBS, and I think the methods are very similar for these types of gene therapies. Having said that, it does involve a neurosurgical procedure, and whenever we're doing a new, you know, any kind of experimental therapeutics, any kind of experimental therapy for any disorder, you have to be concerned about potential side effects, and even unknown potential side effects. And so I think if you choose to do a clinical trial of a gene therapy, just like if you chose to do a clinical trial, really, of any therapy, you just need to be aware that there may be unknown potential adverse effects, and you just need to go in with your eyes open

Dan Keller 13:27 on the other side of the equation. Besides enhancing the function of dopamine or its production, it's thought that alpha synuclein leads to destruction of dopamine producing neurons. Is there any thought of silencing some alpha synuclein production? There's now small interfering RNAs, which are used and approved therapeutically for controlling blood pressure and cholesterol levels, and things like that. Would these be useful drugs to slow down or stop the progression by limiting the amount of alpha synuclein produced.

Dr. Andrew Feigin 14:05 Yeah, that's an excellent question. And I think one of the most exciting potential uses of gene therapy in Parkinson's disease might be to reduce or knock down the production of alpha synuclein. It's known that even normal alpha synuclein, non-mutated alpha synuclein, like the normal alpha synuclein protein. If you have what's called a duplication, meaning if you have too many genes or a triplication, even more copies of the alpha synuclein gene, it increases the risk for Parkinson's disease, even if it's the normal alpha synuclein, without a mutation. And there are multiple other lines of evidence that alpha synuclein, as you mentioned, is involved in the what we call the pathogenesis, the cause of Parkinson's. I think that there's quite compelling evidence that if you could reduce alpha synuclein in the brain, you could have a positive impact on the progression of Parkinson's. And I think there are many techniques with gene therapy that could be used to reduce the per. Direction of alpha synuclein. I'm aware that there are biotech and pharma companies working on some of these therapies. You mentioned RNAi, or what's called RNA interference. That's one approach that is being pursued by several pharmaceutical companies. There's another approach called antisense oligonucleotides, and that's another form of gene therapy that can be introduced not only through surgical procedure, but through even in through a spinal tap, actually, and that can reduce the production of specific proteins that they're designed to target, and so it is conceivable that an antisense oligonucleotide for alpha synuclein could reduce the production of alpha synuclein and potentially have a positive impact on Parkinson's disease, and then perhaps even more interesting to me would be there's a class of medications for which there is an example of an approved therapy for neurologic disease called spinal muscular atrophy called RNA splice modulators. These are drugs that are given by mouth, they're oral medications you take by mouth, and they go into the brain and they can target specific sequences to reduce the way RNA is spliced. RNA is the messenger that takes the code from DNA and translates it into the production of a protein, and if you can change the way the RNA is spliced to make it look like a nonsense RNA, it will just be degraded and will reduce the production of the alpha synuclein, so I don't actually know of a specific example of a biotech or pharma company that has developed this type of therapy, but these kinds of therapies are being developed for other conditions, and would not be surprised if there are companies out there developing these kinds of therapies, and I think that's a hypothesis that really needs to be tested in Parkinson's disease, because it makes a lot of sense to me that people with Parkinson's disease could benefit from a therapy that could reduce alpha synuclein, and there are tools of gene therapy that could potentially do that. So, it seems like a logical way to go.

Dan Keller 16:57 I suppose that would also apply to Lewy body dementia, or dementia with Lewy bodies, since alpha synuclein plays a role there too.

Dr. Andrew Feigin 17:06 Yeah, and other alpha synuclein-based diseases, such as multi-system atrophy, as well.

Dan Keller 17:13 What about genes that raise the risk of Parkinson's disease? I think there's a handful of about seven of them, and more coming along, would those be a target, or do they so rarely influence development of the disease in such a small population that they wouldn't be targeted?

Dr. Andrew Feigin 17:30 Yeah, so the gene mutations that have been firmly associated with increasing risk of Parkinson's disease, I think, could be targets of gene therapy for individuals with those gene mutations of the known gene mutations that are associated with Parkinson's disease, they count for about 15% of patients. There's a rough estimate, roughly 15% of patients with Parkinson's disease. So that's not trivial, and actually those therapies fall into the category of what I guess we would call precision medicine. If you have a gene mutation, for example, in the GBA gene, which is one of the more common known genetic causes of Parkinson's disease, then potentially that could be targeted with a type of gene therapy. We think of most of the gene mutations in GBA. There's some controversy about this. The gene mutations in GBA that cause Parkinson's disease, we think of as loss of function, they're making the GBA protein not function normally. So, if you could introduce more of the normal functioning GBA by doing gene therapy with the GBA gene, theoretically you could improve the parkinson's and slow the progression of the parkinson's in patients who carry the GBA mutation, and the same goes for another gene mutation that's associated with Parkinson's disease, called Lark two that you could target specifically people with Lark two gene mutation to try to alter the manifestation of that gene and to affect the disease in patients with the Lark two gene mutation. So I wouldn't dismiss that. I think those are therapies that can and will be pursued, and the other ones you mentioned, by the way, there's another way of thinking about these gene mutations that I think gets at the answer to your question. So, we talked about the six or seven gene mutations that are known to be associated with Parkinson's disease, but there's a type of way of analyzing DNA that's called GWAS, genome-wide association studies, and when people have done these studies over the years, you look through the entire genome, and you look for variants in genes that seem to alter the risk of getting Parkinson's disease, and these GWA studies, genome-wide association studies, have actually identified genetic variants in about 200 locations in the human genome that seem to alter risk for Parkinson's disease, and so these are all potential targets, you know, so we don't really know how common all of them are. They seem to alter the risk for Parkinson's disease, and it's quite possible that some variant could give a hint to what the underlying pathophysiology of Parkinson's disease that might be more widely applicable to more people with Parkinson's disease, so these kinds of. These are important, and could lead to novel approaches to gene therapy for patients with Parkinson's disease.

Dan Keller 20:07 On this topic of gene therapy, if we missed anything important or anything interesting to add,

Dr. Andrew Feigin 20:13 I think the main point is the one that you brought up with your question about alpha synuclein. To me, that seems like the most obvious target, and something that I expect that we will start to see in the next year or longer, maybe next several years, gene therapies entering human trials that are targeting lowering alpha synucleins. If that's, I think, would be a major take-home message. I would say

Dan Keller 20:38 very good, you've covered a lot of ground, and I'm sure it'll be interesting to our audience to keep watching this area. So, thanks.

Dr. Andrew Feigin 20:46 Yeah, happy to do it. Thanks for inviting me.

Dan Keller 20:57 As Dr. Feigin described, gene-based therapy is a rich and multidimensional area of research for Parkinson's, which goes beyond merely replacing or fixing a faulty gene. To recap some of his points, there is a possibility that genes can be manipulated in a way that can enhance dopamine levels and production, as well as diminish the production of alpha synuclein. If you want to hear more about gene-based therapy, look for our previous podcast titled Gene Based Therapies for Parkinson's disease with Dr. Roger Barker. You can also find out more by searching our website@parkinson.org for gene therapy, among the information is an article on the Foundation's PD Generation Study, a national initiative offering genetic testing and counseling for people with Parkinson's. If you want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback's if you enjoyed this podcast, be sure to subscribe and rate and review the series on Apple Podcasts or wherever you get your podcasts. We would like to take a moment to thank Blue Rock Therapeutics for their generous support of the mission of the Parkinson's Foundation. 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'll be bringing you a new episode in this podcast series every month. Till next time, for more information and resources, visit parkinson.org's or call our toll-free helpline at one 804 PD info, that's 1-800-473-4636 Thank you for listening.

Dr. Andrew Feigin is a Movement Disorders neurologist and Professor of Neurology at NYU Langone Health, where he is the Director of the Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders. He has been involved in clinical research for Parkinson’s disease and related disorders for more than 25 years, and he has been a site principal investigator on more than 30 National Institute of Health and industry-sponsored clinical trials of new treatments for Parkinson’s disease (PD) and Huntington’s disease (HD). In addition, Dr. Feigin has had leadership roles in several early phase clinical trials and advanced multicenter clinical trials. In addition to his research interests, Dr. Feigin has remained a committed and busy clinician caring for patients with PD and related movement disorders.