Stanford PD Community Blog

Stanford Parkinson's Community
  • Home
You are here: Home / Webinars - Announcements & Notes / Gene Therapy and Parkinson’s Disease – Webinar Notes

Gene Therapy and Parkinson’s Disease – Webinar Notes

October 26, 2020 By Parkinson's Community Help

“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

Advantages:

  • 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

Disadvantages:

  • 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

Advantages:

  • 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

Disadvantages

  • 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 (clinicaltrials.gov 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 clinicaltrials.gov, 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 trials.gov 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.

Filed Under: Webinars - Announcements & Notes

  • Home

Categories

  • Monthly List – PD Webinars
  • Webinars – Announcements & Notes
  • Monthly List – Caregiving Webinars
  • Monthly List – Support Groups
  • Support Groups – Meetings & Notes
  • News
  • Research
  • Events
  • Exercise
  • Comment

Top Pages of the Stanford Parkinson’s Community Outreach Website

  • List of Live, Virtual PD Exercise Classes
  • List of PD Exercise Videos
  • Symptoms of PD
  • For Those Newly Diagnosed
  • Support Resources for PD

Featured Posts

Your top three Parkinson’s questions answered by the APDA

The American Parkinson Disease Association (APDA) recently shared the top three questions they are … [Read More...]

National Day of Action – Thursday, September 22, 2022

From the American Parkinson Disease Association, Northwest Chapter (APDA NW), Tuesday, September … [Read More...]

Archive

  • February 2023 (3)
  • January 2023 (4)
  • December 2022 (7)
  • November 2022 (4)
  • October 2022 (9)
  • September 2022 (2)
  • August 2022 (3)
  • July 2022 (5)
  • June 2022 (6)
  • May 2022 (9)
  • April 2022 (5)
  • March 2022 (8)
  • February 2022 (5)
  • January 2022 (13)
  • December 2021 (7)
  • November 2021 (19)
  • October 2021 (14)
  • September 2021 (12)
  • August 2021 (9)
  • July 2021 (7)
  • June 2021 (10)
  • May 2021 (10)
  • April 2021 (16)
  • March 2021 (8)
  • February 2021 (27)
  • January 2021 (18)
  • December 2020 (18)
  • November 2020 (19)
  • October 2020 (13)
  • September 2020 (7)
  • August 2020 (12)
  • July 2020 (15)
  • June 2020 (13)
  • May 2020 (17)
  • April 2020 (14)
  • March 2020 (14)
  • February 2020 (5)
  • January 2020 (12)
  • December 2019 (10)
  • November 2019 (6)
  • October 2019 (6)
  • September 2019 (7)
  • August 2019 (5)
  • July 2019 (10)
  • June 2019 (3)
  • May 2019 (8)
  • April 2019 (10)
  • March 2019 (5)
  • February 2019 (9)
  • January 2019 (12)
  • December 2018 (2)
  • November 2018 (8)
  • October 2018 (10)
  • September 2018 (2)
  • August 2018 (7)
  • July 2018 (10)
  • June 2018 (9)
  • May 2018 (3)
  • April 2018 (10)
  • March 2018 (4)
  • February 2018 (8)
  • January 2018 (11)
  • December 2017 (11)
  • November 2017 (5)
  • October 2017 (11)
  • September 2017 (10)
  • August 2017 (7)
  • July 2017 (13)
  • June 2017 (10)
  • May 2017 (14)
  • April 2017 (12)
  • March 2017 (17)
  • February 2017 (11)
  • January 2017 (13)
  • December 2016 (4)
  • November 2016 (6)
  • October 2016 (1)
  • September 2016 (11)
  • August 2016 (5)
  • July 2016 (8)
  • June 2016 (4)
  • May 2016 (2)
  • April 2016 (2)
  • March 2016 (1)
  • February 2016 (1)
  • January 2016 (4)
  • December 2015 (1)
  • November 2015 (2)
  • October 2015 (3)
  • September 2015 (1)
  • August 2015 (3)
  • July 2015 (1)
  • June 2015 (1)
  • May 2015 (1)
  • April 2015 (2)
  • March 2015 (4)
  • February 2015 (2)
  • January 2015 (1)
  • December 2014 (1)
  • November 2014 (2)
  • October 2014 (1)
  • September 2014 (2)
  • August 2014 (2)
  • July 2014 (1)
  • June 2014 (5)
  • May 2014 (1)
  • April 2014 (2)
  • March 2014 (3)
  • February 2014 (1)
  • January 2014 (1)
  • December 2013 (1)
  • November 2013 (1)
  • October 2013 (1)
  • September 2013 (1)
  • August 2013 (1)