The Future of Parkinson’s Disease Treatments – UPDATE

The Parkinson’s disease (PD) research community is extremely eager to find a medication that is disease modifying or neuroprotective (meaning it protects the nerve cells from damage or degeneration). There have been many attempts over the past number of years to demonstrate through clinical trials that particular compounds have neuroprotective effects but to date, these attempts have not been successful.

Potential Neuroprotective Strategies for Parkinson’s

In a prior blog, and elaborated upon in a recent webinar, a number of potential neuroprotective strategies were discussed. Excitingly, all these strategies have led to the development of compounds that are currently in clinical trial. These include:

  • Targeting abnormal alpha-synuclein aggregation
  • Increasing activity of GLP-1, a strategy which may block activation of immune cells in the brain
  • Increasing the activity of the enzyme glucocerebrosidase to enhance the cell’s lysosomal or garbage disposal system
  • Decreasing activity of the proteins LRRK2 or c-Abl to decrease neurodegeneration

There is evidence that exercise may be neuroprotective as well.

It’s time for an update because, beyond the strategies mentioned above, there are other neuroprotective strategies that are in various stages of clinical development that I have not yet covered. Of note, I want to highlight The Parkinson’s Hope List, which is maintained by Dr. Kevin McFarthing, a former biochemist, and person with Parkinson’s who is based in the UK. The list is a collation of all the compounds that are being explored as new therapies for PD at all stages of the research pipeline and is updated frequently. It is an excellent source of information for those interested in the current state of PD research focused on new potential treatments.

All the strategies mentioned below have been or are being tested in people which is exciting because that indicates that they are making progress. I will explain four of them below. (Many other strategies are in pre-clinical phases and are being studied in cells or animal models, but not yet in people).

Neurotrophic factors

This first approach is more extensive than the others and thus requires more explanation. Neurotrophic factors, or nerve growth factors, are proteins which enhance the survival of nerve cells. There are two strategies for introducing nerve growth factors into the brain that are being explored:

Direct infusion of glial cell line derived neurotrophic factor (GDNF) into the brain.

The strategy of infusion GDNF directly into the brain has been studied in a number of clinical trials since the early 2000s. The most recent study was published in 2019 and presented the results of a trial that surgically implanted a specially designed delivery system into the brains of 35 people with PD. The study lasted 40 weeks and was placebo controlled – which means half the participants received the medication and half underwent all the steps of the infusion but did not receive medication. The two groups were compared and these results were published in the journal Brain. Although there was a trend toward improvement in the treatment groups as compared to the placebo group when evaluated off of medication, the trend was not statistically significant and therefore the trial did not ultimately prove that GDNF infusion was helpful for symptoms of PD.

Despite this disappointment, there were some intriguing findings which suggest that further study is warranted. A post-hoc analysis of the participants (that is, statistical tests that were not pre-planned before the trial) showed that in nine patients who received the treatment, and in none of the patients who received the placebo, there was a statistically significant improvement in their symptoms. This may suggest that certain people with PD may benefit from the treatment and more research is necessary to understand who those people may be. In addition, PET imaging demonstrated increased uptake of dopamine in the treated group and not in the placebo group. The uptake in dopamine took place, in some cases, in the entire putamen which suggests that the unique delivery system that was developed for this trial worked as designed.

Gene therapy

Introduction of GDNF into the brain using gene therapy. 

Gene therapy is a category of treatments that involve introducing DNA into cells to alter which proteins are created and thereby improve symptoms or even cure disease.

How gene therapy works:

A virus is a tiny bundle of genetic material that is able to penetrate a cell and hijack the cell’s machinery to replicate its genes, as well as produce viral proteins, often causing disease in the process. Scientists cleverly take advantage of these processes to drive gene therapy. The harmful pieces of DNA are removed from the virus and a gene of choice is incorporated into the viral structure. Then the modified virus is injected into a specific part of the body, thereby allowing it to “infect” cells. If all goes according to plan, the gene that was incorporated into the modified virus is used by the cell’s machinery to make the designated protein.

In the case of GDNF, this process is used to drive the brain to make more nerve growth factor.

Clinical trials are underway which introduce GDNF into the brain using gene therapy techniques. This trial is recruiting patients for GDNF gene therapy. Another trial is no longer recruiting and hopefully will be able to share data soon.

Three additional strategies for Parkinson’s disease treatments

A number of other strategies for neuroprotection are being investigated with compounds that are currently in clinical trial.

CCR3 inhibitor

CCR3 is a receptor for a group of molecules that attract inflammatory cells to the site of an infection. Inhibiting this process may decrease inflammation and may have a positive impact on various conditions including Parkinson’s disease. AKST4290 is a compound that inhibits CCR3 and was recently in clinical trial for PD.

Ursodeoxycholic acid (UDCA)

Dysfunction of the mitochondria, the energy producing machinery of the cell, is thought to play a major role in the development of PD. UDCA (which is approved for use in people for a relatively rare liver condition known as primary biliary cholangitis) was identified in a drug screen as a promising compound to improve mitochondrial function. It is currently in clinical trial for PD.

Stearoyl CoA desaturase (SCD) inhibitor

SCD is an enzyme that is involved in lipid metabolism, producing an array of lipid molecules that control a range of cell functions. Interestingly, SCD is regulated by SREBF1, which has been identified in genetic screens as a risk factor for PD. In pre-clinical work in mice and cell culture, inhibiting the SCD enzyme was associated with a variety of cellular changes as well as increased neuron survival. A phase 1 clinical trial took place in the Netherlands and the medication was found to be well-tolerated and safe.

Tips and Takeaways

  • The scientific community is focused on finding a neuroprotective agent for PD, that slows down disease progression
  • A number of strategies have already been presented in a prior blog
  • APDA funds cutting edge pre-clinical work which is vital for discovering the compounds that can be tested in clinical trial. Check out what we fund.
  • Additional strategies that are being tested in people that may provide neuroprotection include GDNF infusion into the brain, GDNF gene therapy procedures, inhibition of inflammation in the brain, improvement of mitochondrial function, and manipulation of lipid metabolism.


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