Target Validation Studies for the Discovery of Novel Small Molecule Therapeutics with the Potential to Modify Disease Outcome by Inhibiting Bacterial Amyloid Protein-induced Alpha-synuclein Aggregation and Associated Neuronal Toxicity

Study Rationale:
Patients with Parkinson’s disease frequently report serious gastrointestinal (GI) symptoms, most commonly constipation, which are not well treated with currently available medicine. Emerging data indicates that dysfunction and death of nerves within the gut (i.e., the enteric nervous system), driven by accumulation of toxic forms of the protein alpha-synuclein, may be the underlying cause of these gastrointestinal symptoms. This program seeks to develop a new experimental system that accurately replicates Parkinson’s disease biology in enteric nervous system cell cultures. The investigators will use it to identify effective new medicines that treat the enteric nervous system and restore normal GI function.

Hypothesis:
We hypothesize that new medicines can reduce the accumulation of toxic forms of alpha-synuclein in gut nerves and return them to their normal function. This will result in improved GI function, offering patients with Parkinson’s disease new and effective treatments for their GI symptoms.

Study Design:
Nerves from the GI tract of mice that have been genetically engineered to over-produce alpha-synuclein will be harvested and grown in culture to produce our model system of the enteric nervous system. We will subsequently challenge these cultures with various environmental stimuli to better understand factors that may accelerate the accumulation of toxic forms of alpha-synuclein . In parallel we will treat these cultures with novel molecules selected from our drug discovery program at Axial Biotherapeutics. Our goal is to identify a drug candidate that has the potential to short-circuit the alpha-synuclein accumulation process, preserve healthy enteric nervous system function, and restore normal GI function in patients with Parkinson’s disease.

Impact on Diagnosis/Treatment of Parkinson’s disease:
Accumulation of toxic forms of alpha-synuclein in the gut may trigger toxic forms of alpha-synuclein to accumulate in the brain. If true, these new medicines have the potential to treat both the GI and movement symptoms experienced by Parkinson’s patients.

Next Steps for Development:
The experimental tools and knowledge gained from this project complements the drug discovery program at Axial Biotherapeutics, which aims to deliver a new drug candidate molecule that can move to clinical trials within the next three years.