Gene Therapy and Parkinson’s Disease – Webinar Notes

Gene Therapy and Parkinson’s Disease – Webinar Notes

“Dr. Gilbert Hosts” is a webinar series sponsored by the American Parkinson Disease Association (APDA), featuring Dr. Rebecca Gilbert, a movement disorder specialist. In September, the webinar speaker, Dr. Tim Greenamyre, gave a thorough overview of gene therapy and Parkinson’s disease (PD), and then answered questions.  We at Stanford Parkinson’s Community Outreach listened to the webinar and are sharing our notes. 

J Timothy Greenamyre, MD, PhD is a man of many hats. At the University of Pittsburgh Medical Center alone, he is a Love Family Professor, Vice Chair of Neurology, Chief of Movement Disorders, Director of the Pittsburgh Institute for Neurodegenerative Diseases, and Director of the APDA Center for Advanced Research. His lab studies mechanisms of neurodegeneration in Parkinson’s with a focus on gene and bio-interactions. Dr. Greenamyre also performs translational studies using pharmacologic and gene approaches.

Here is a link to the webinar, and below are my notes.

– Cassandra Irizarry


Gene Therapy and Parkinson’s with Tim Greenamyre

September 16, 2020

Webinar hosted by the American Parkinson Disease Association

Summary by Cassandra Irizarry, Stanford Parkinson’s Community Outreach

Principles of Gene Therapy

What is a gene?

  • A piece of DNA from one of our chromosomes that gives cells instructions on how to make a particular protein, in a particular cell, at in a cell at a particular time

What is gene therapy?

  • A way to replace a gene or protein that is defective or deficient OR
  • A way to “turn off” a gene that is abnormally overactive or reduce a protein that is abnormally abundant

How is gene therapy delivered?

  • Genes to augment or replace a function are usually “packaged” in an adeno-associated virus (AAV)and is injected into the brain
  • Gene therapy designed to turn something off or down is usually an “antisense oligonucleotide” (ASO) delivered via spinal tap (lumbar procedure)
    • Advantages: Good for targeting specific neurotransmitters (like dopamine cells, for example). It’s also a  “one and done” therapy, and not permanent.
    • Disadvantages: ASO can’t be injected throughout the whole brain, only to treat a specific area or symptom(s). It required multiple treatments.
  • It takes months after a procedure for the gene to behave we want it to

Advantages and Disadvantages of Gene Therapy


  • Using a virus for delivery allows for the targeting of specific brain regions and cell types
  • Because it’s injected directly into the brain, the “blood/brain barrier” is not an issue
  • May be a “one-and-done” therapy


  • Generally permanent (no way to turn it off)
  • PD affects many parts of the brain and body, so delivery to a specific region (like dopamine neurons) may have limited impact

Antisense Oligonucleotides- A Special Case


  • Can affect widespread areas of the brain and body
  • Effects of each treatment infusion (spinal tap) wear off over months, so the effect is not permanent- this can be good if there are side effects


  • The effect is not permanent; may require multiple treatments

Gene therapy strategies for PD

  • Symptomatic treatments treat the symptoms of PD
  • Disease modification treatments (aka neuroprotection) try to alter the course of disease and/or stop progression

Current clinical trials evaluating gene therapy in PD

  • SUNRISE PD ( identifier: NCT03720418)
  • GDNF Gene Therapy (NCT04167540)
  • PROPEL (NCT04127578)
  • RESTORE-1 (NCT03562494)
  • REASON (NCT03976349)

None of these trials is in Phase III.  NCT numbers provide more info about the trial.

Question & Answer

If I’m a person with PD and interested in these trials, how can I join one?

Dr. Greenamyre: If you’re uninitiated, it’s hard to find and get started with trials. There are two resources I’d suggest. One is, where you can search for trials for PD, and for which are open- but it’s a little hard to navigate that website. There’s another website called the Fox Trial Finder, which will take you through a series of questions related to your symptoms, guide you to where the trials are, and show you who’s eligible and non-eligible.

Will the use of gene therapy be subject to all phases of clinical trials?

Dr. Greenamyre: Yes, gene therapy will undergo the same kind of approval process. Phase l trials monitor for safety and adverse events. Phase ll trials are designed to look for effectiveness, but are small. The really crucial phase- Phase lll- typically involves thousands of patients can cost thousands of dollars. Phase III trials seek to show a new treatment is more effective than treatments currently available.

What are your thoughts on the best stage of PD to use gene therapy? Is it better for early or advanced PD?

Dr. Greenamyre: It really depends on the kind of therapy you’re talking about. In the AADC trial, designed to make levodopa more effective and last longer, you have to wait until the stage you’re already taking and needing to take levodopa. On the other hand, if you’re looking at something designed to slow down the disease, then the earlier the better. A limitation we have in these trials is how early we can diagnose PD. We typically have to wait until people develop the typical motor symptoms, and we know by this point that their disease has been going on a long time.

Can you imagine a day where people are diagnosed very early (before motor symptoms) and can receive gene therapy at that point?

Dr. Greenamyre: Yes- if we could slow or stop the disease at the earliest point, before motor symptoms develop, people’s quality of life would still be improved moving forward.

If I have gotten Deep Brain Stimulation (DBS) already, would I be eligible for gene therapy?

Dr. Greenamyre: There’s no theoretical reason why not. But, on a practical basis, while trials are ongoing, they have to have participants in the trial who have not had surgical manipulations that are permanent, such as DBS. So if you’ve had DBS, you’re not eligible for a gene therapy trial, to the best of my knowledge. But once the gene therapies are on the market, there’s no reason you couldn’t get it.

Are symptomatic and disease-modifying therapies the same in procedure the same?

Dr. Greenamyre: Theoretically, they could be the same. Symptomatic therapies look at specific symptoms (whether it be tremor or slowness, those kinds of things), and measures those. Disease-modifying (or neuroprotective) therapies look at things over a longer time scale. And we use certain rating scales to tell the stage of the patient; or PET scans- we use those things as measurements of what changes over time. Both kinds of trials can be administered in the same way, but what is measured at the end will be different.

What, in your opinion, is a likely timeline for gene therapy approval?

Dr. Greenamyre: I don’t know- I’d say we’re at least 5-7 years from having something approved. The exception is the ADC trial, which is in Phase II which has shown positive results up until this point.

Are there gene therapy trials in other countries that are more advanced?

Dr. Greenamyre: The trials that we listed are international. The first listed (SUNRISE PD) is in the UK and France- the other trials are mostly in the US, but the REASON-1 trial is international-US, France, Spain, and some other countries are participating. Clinical tells you where the trials come from.

Where does the injected material of gene therapies come from? What’s the difference between gene therapy and stem cell therapy?

Dr. Greenamyre: The genetic material is made in a lab- in a test tube, basically. It’s identical generally to what’s in the brain. The genetic material is not rejected; the viruses are harmless and generally don’t cause any kind of reaction, and are designed and engineered to do that. It could theoretically cause an inflammatory response, but the viruses used have been quite safe.

Gene therapy takes a biological molecule (DNA or something close), and uses that. Stem cell therapy is using cells (often from the patient) that are manipulated and injected back. If the cells come from a different source, there’s a risk they could be rejected. If they come from the same person, there’s very little chance of rejection, because it’s their own cells. It depends on the source of the cells, or genetic materials in gene therapy.

Are there gene therapy trials for Parkinson’s plus syndromes or related neurodegenerative diseases?

Dr. Greenamyre: I’m not aware of gene therapy trials for MSA or PSP or other related PD syndromes. There’s no reason it can’t be done, but there is work on trying to protect the brain in PSP and MSA, just not with gene therapy. There’s certainly hope for these diseases, but research is a little bit behind PD research.

How do researchers decide which genes to target?

Dr. Greenamyre: We used to think that PD had no genetic component whatsoever, but now we recognize there’s lots of genetic factors that go into it. Some gene therapies are based on genes that we know that, when mutated and functioning abnormally, cause PD. We take those clues and test them in animal models of PD and look for signs they’re effective there, and then translate them into therapies for people. It also comes from what we know about the chemistry and cell biology of PD. Therapies trying to restore dopamine come from decades of research on dopamine pathways that we try to restore. Some strategies come from what we know about what causes nerve cells to die in PD. If we know this, we can target the therapy: first using cells in a dish, then in animal models- and then, if it looks promising, in humans.

Can you define “translational research” for us?

Dr. Greenamyre: There’s a difference between basic research and clinical practice. For years, scientists studied cells in a dish or using animal models of disease, working out the mechanisms that lead to cell death and then leaving it at that. There was no translation of that knowledge into clinical practice. What we’ve tried to do in recent years is to translate that knowledge that comes from the lab into something that might be useful clinically. We take these lab results and target them into strategies we think could be useful clinically. Translation is the critical bridge between basic scientific knowledge and clinical practice.

When a trial enters Phase III, do you foresee the surgery (injection into the brain) dissuading people from participating?

Dr. Greenamyre: I think it’s very individualized and that it depends on both the therapy and the potential of that therapy. I think there are people who are naturally reluctant to have their brain operated on for a medicine offering only moderate benefit- but if the therapy stops the disease in its tracks, its conversation around participation changes. It’s a very individual decision. Another aspect of this is whether the flavor of gene therapy is one-and-done or requires multiple injections, which might scare some people off, but not others. It really depends on motivational factors and how the researcher explains it to them.

Can you explain CRISPR for PD/ gene therapy?

Dr. Greenamyre: CRISPR is a way to do gene editing. Now, we’re not changing the gene defect in the person. We can replace the gene, but the person still has the abnormal gene in the brain. CRISPR is a way to correct the cells in the brain rather than inject another gene to replace it. It has potential for genetic diseases that we can predict before birth. To do this in an adult’s brain is much more complex, and I don’t think we have the technology to do that right now. I think it holds a lot of potential, but it’s not the right time.

Gene therapy needs to be targeted. How does that location relate to where Lewy bodies are, and is there any benefit in knowing where a person’s L bodies are to potentially target those?

Dr. Greenamyre: Lewy bodies are abnormal clumps of protein that accumulate in the brain in PD and Lewy body dementia, causing toxicity in the cells. In PD, much Lewy body biology is contained in the dopamine neurons. We expect that to be helpful for protecting those dopamine neurons, but we know Lewy bodies are more widespread and can affect general cognitive function. Right now, gene therapy injections couldn’t target all at once. ASO (antisense oligonucleotide) gets more widespread dispersion, so it depends on the specific therapy.