Alpha-Synuclein-Expression-Lowering Therapeutics: Initial Pre-Clinical Development
Research Grant, 2013
Objective/Rationale: † † † † † ††
Increased dosage of the alpha-synuclein gene is linked to Parkinsonís disease (PD). Out of 1,126 FDA-approved compounds and health supplements screened, we identified a small number of preliminary hits that modulate the expression of endogenous neuronal alpha-synuclein micro RNA abundance in cultured neuroblastoma cells.
Project Description: † † † † † ††
Here we will pre-clinically develop these preliminary hits.
- We will evaluate the effect of these hits specifically on endogenous alpha-synuclein protein.
- We will delineate their in vivo pharmacokinetics and brain penetrance.
- We will determine whether a prioritized hit lowers the expression of endogenous alpha-synuclein in the PD-vulnerable substantia nigra of pre-clinical models.
- We will perform a counter screen to assess for off-target effects.
Relevance to Diagnosis/Treatment of Parkinsonís Disease: † † † † † † † † † ††
Compounds that lower endogenous alpha-synuclein expression will be useful probes for dissecting the pathobiology of Parkinsonís and may serve as stepping stones for novel therapeutics.
Anticipated Outcome: † † † † †
Our novel and cause-directed approach may delineate compounds that lower expression of endogenous human alpha-synuclein in pre-clinical models.
This study highlighted a class of alpha-synuclein (SNCA) expression-lowering chemicals in human neuroblastoma cells, primary cortical neurons, as well as in pharmacokinetic and efficacy trials in pre-clinical models. Moreover, by correlating systems pharmacology, gene silencing, endogenous gene and protein expression with quantitative chromatin immunoprecipitation analyses, we delineated a druggable, receptor-mediated pathway regulating the transcription of endogenous SNCA.†
Head of the Neurogenomics Lab and the Parkinson Personalized Medicine Initiative at Harvard and Brigham and Womenís Hospital
Associate Professor of Neurology at Harvard Medical School
Location: Cambridge, Massachusetts, United States