Alpha-synuclein is a sticky protein that clumps in the brains of people with Parkinson's disease (PD). Duplication or triplication of SNCA, a gene responsible for the production of alpha-synuclein, leads to inherited PD. Additional copies of SNCA produce excess of alpha-synuclein, promoting neurodegeneration and increasing the severity of Parkinson's symptoms. We propose to limit the production of alpha-synuclein by blocking translation, a step in the process of protein production from the DNA template. Our most promising therapeutic compound, Syn-516, has already been tested for the ability to block the translation of SNCA and to reduce the amount of alpha-synuclein in dopamine-producing nerve cells.
We will investigate how Syn-516 blocks the production of alpha-synuclein in vitro in dopamine-producing cells and subsequently in vivo in the substantia nigra -- a dopamine-producing brain region implicated in PD -- of pre-clinical models with Parkinson's features. Our ultimate aim is to determine the ability of Syn-516 to improve movement and gait in the pre-clinical models of Parkinson's.
We will evaluate how Syn-516 and similar compounds block the production of alpha-synuclein in vitro in dopamine-producing nerve cells. We will determine the optimal doses of the compound (both taken by mouth and injected), how the drug travels through the body and whether it can pass into the brain from the blood. Our goal is to compare Syn-516 or a similar compound with other drugs that reduce the amount of alpha-synuclein to determine whether it's sufficiently effective against alpha-synuclein in dopamine-producing nerve cells to warrant its testing in a more advanced model of Parkinson's disease.
Impact on Diagnosis/Treatment of Parkinson's disease:
Currently available Parkinson's treatments counteract disease-related changes near the ends of nerve cell processes. The treatment we are developing would do the opposite: It would block the production of alpha-synuclein in the body (center) of the nerve cell. The treatment would prevent alpha-synuclein buildup and clumping and would ultimately shut down this disease-causing process, providing the maximal therapeutic effect.
Next Steps for Development:
If Syn-516 or a similar compound proves to be potent in our dopamine-producing cell models, we will test its ability to improve gait and slow or stop disease-related changes in the brain in the most suitable pre-clinical model with Parkinson's features. Following pre-clinical evaluation, we will test its safety in a Phase I clinical trial.