Vaccines & Medications Targeting Alpha-Synuclein: Latest Parkinson’s Disease Research

APDA Research Vaccines & Medications Targeting Alpha-Synuclein: Latest Parkinson’s Disease Research

New treatments for Parkinson’s disease

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Did you know that many pharmaceutical companies are working on vaccinations and other potential new treatments for Parkinson’s disease (PD)?  Each clinical trial and study that is underway is teaching us something new and important that will hopefully get us closer to a successful outcome.

Research into potential new medications targeting alpha-synuclein, a key protein involved in Parkinson’s disease progression, remains very active. Multiple new medications in various stages of research, from antibodies to vaccines to small molecules are aiming to treat and slow down Parkinson’s disease.

In past blogs, we have reviewed the various mechanisms of action that are being studied to see if they result in successful slowing of disease progression. This may be helpful background reading if you’re interested in learning more about this topic.

You can view these past blogs below:

What is alpha-synuclein and how is it related to Parkinson’s disease?

People with PD have protein deposits in their brain, known as Lewy bodies, which are composed of abnormally accumulated alpha-synuclein. It is thought that this accumulation plays a role in nerve cell death in PD and that preventing alpha-synuclein aggregation and dissolving pre-formed aggregates may be an effective approach to slowing down the progression of PD.

Read more about Lewy Body Dementia

It is important to know that a related disease, Multiple system atrophy, is also caused by abnormal accumulation of alpha-synuclein and the same alpha-synuclein anti-aggregation strategies are tested in these patients as well.

Current treatment approaches that target α-synuclein

Today we will explore various compounds with different mechanisms of action – all with the common goal of decreasing aggregation of alpha-synuclein.

Alpha-synuclein antibodies (passive immunity)

There are multiple research efforts to create and test antibodies against alpha-synuclein as a treatment for PD, also known as passive immunity. The antibodies work by binding to alpha-synuclein, preventing its ability to aggregate, as well as aiding in aggregate removal. The following antibodies are currently being investigated in clinical trials:

  • The prasinezumab antibody

This antibody was studied in a Phase 2 trial called PASADENA, with 316 participants, all with newly diagnosed PD who had mild symptoms and were not on any medication for PD. The trial was double-blinded and placebo controlled and did not meet its primary endpoint which was a change in the total Movement Disorder Society-United Parkinson’s Disease Rating Scale (MDS-UPDRS). But it did show an improvement in Part 3 of the MDS-UPDRS, which measures the clinician’s rating score of the motor symptoms on neurologic exam, with the group that received the antibodies faring better.

The trial continued into an open label extension period, in which the trial participants were followed, and their motor scores were compared to an external control group. The results of this analysis were recently published, and the PASADENA group continued to showed a slower decline on the MDS-UPDRS Part 3.

A second Phase 2 trial of this antibody called PADOVA is currently underway, in people with PD with more advanced symptoms than those enrolled in PASADENA.

  • MEDI -1341/TAK-341

This antibody was studied in Phase 1 trials and is now in a Phase 2 trial for people with Multiple system atrophy with an estimated completion date of August 2025.  

  • Lu-AF82422 

This antibody was studied in a Phase 1 trial and then in a Phase 2 trial for people with Multiple system atrophy. Results of the Phase 2 trial were presented in March 2024. The trial showed a trend toward improvement but missed statistical significance. Lundbeck (pharmaceutical company) has stated that they may run a Phase 3 trial of this antibody.

Alpha-synuclein vaccine (active immunity)

The introduction of a molecule that induces the body to produce its own antibodies against alpha-synuclein is known as active immunity. The hypothesis is that the antibodies that the body produces bind to alpha-synuclein and prevent its ability to bind to other alpha-synuclein molecules and form aggregates. The following vaccines are being investigated:

  • ACI-7104.056

Two related vaccines PD01A and PD03A were tested in Phase 1 trials and further development appeared to be halted until PD01A was acquired by AC Immune (a biopharmaceutical company). A Phase 2 trial studying an optimized formulation of the vaccine began in July 2023 and is now underway.

  • UB312

Developed by Vaxxinity (a biotechnology company), a Phase 1 study of this molecule was completed, and results were published in 2024. The paper showed that the participants who received UB312 had detectable antibodies to alpha-synuclein in their serum and cerebral spinal fluid (CSF). In addition, those who received UB312 demonstrated less alpha-synuclein in their CSF as determined using the synuclein seeding amplification assay.

Additional antibodies were studied in clinical trial, including ABBV-0805 and BIIB054, but the companies who were developing these compounds made the decision not to continue the investigation.

Molecules that block alpha-synuclein aggregation

Small molecules have been developed that work to stop alpha-synuclein accumulation or enable its breakdown. These include:

Small molecule inhibitors of alpha-synuclein aggregation

Other small molecules affect alpha-synuclein in various ways

  • Buntanetap suppresses the translation of DNA into messenger RNA (mRNA) of several neurotoxic proteins. This group of neurotoxic proteins produces insoluble clumps that accumulate in nerve cells, disrupting the cell’s normal function. One of these proteins is alpha-synuclein, which abnormally accumulates in PD.  In early studies, buntanetap showed reduction of inflammation and preservation of axonal integrity and synaptic function. A Phase 3 trial of buntanetap in early PD was just completed and results showed improvement in cognition and motor scores in certain subsets of Parkinson’s patients.
  • Enterin/ENT-01/Kenterin displaces membrane-bound alpha-synuclein aggregates from nerve cells. It was tested as a treatment for constipation in a Phase 2 trial which showed positive results. A recent trial for Parkinson’s disease dementia however, was stopped early without results.
  • LY3962681 is a small interfering RNA (siRNA) that binds alpha-synuclein messenger RNA (mRNA) and causes it to breakdown. By reducing mRNA, its protein product of alpha-synuclein is reduced. It is currently being studied in a Phase 1 trial

APDA funding and alpha-synuclein aggregation

APDA funding continues to expand our understanding of alpha-synuclein aggregation and how potential treatments can interfere with that aggregation.

  • Dr. Helen Hwang is developing cell-based assay to test whether potential drug candidates can prevent the accumulation of a-syn fibrils.   
  • Dr. Brianne Rogers is exploring the regulatory elements controlling gene expression of SNCA, the gene that encodes alpha-synuclein, with the goal of identifying new therapeutic targets for PD. 
  • Dr. Patricia Aguilar-Calvo is working to understand how heparan sulfate proteoglycans, large molecules that are attached to the outside of cells, modulate the propagation and clearance of alpha-synuclein aggregates in the nervous system. 

Tips & Takeaways

  • Abnormally aggregated alpha-synuclein plays a key role in the pathology of PD
  • A key strategy of many potential medications for PD which are in clinical trial is interfering with the ability of alpha-synuclein to form aggregates
  • Alpha-synuclein antibodies, alpha-synuclein vaccines, small molecules that interfere with alpha-synuclein binding, as well as other strategies that decrease alpha-synuclein production are being tested in clinical trial.
  • To help further important PD research, please consider making a gift today.

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