Objective/Rationale:
Parkinson’s disease has multiple genetic and environmental causes. As a result, therapeutic efforts aimed at a single cause of the disease may have limited value. ShanaRx has identified a common downstream pathway that is predicted to play a key role in both the sporadic and familial forms of PD. ShanaRx is developing and testing the safety and efficacy of drugs that activate this pathway.
Project Description:
ShanaRx will target a major signaling pathway in neurons called the PI3K pathway. This pathway has been specifically implicated in PD by human genetic mutations associated with the disease. Moreover, activation of the PI3K pathway by genetic or pharmacological tools was found to be protective in multiple animal models of Parkinson’s disease, stroke, Alzheimer’s disease and spinal cord injury. ShanaRx has identified a novel class of compounds that activate this pathway. Initial studies these compounds are protective in a tissue culture dish and in ameliorating advanced PD symptoms associated with dopamine replacement therapy. Here we propose to test ShanaRx compounds for safety, stability, oral availability and efficacy in animal models of PD.
Relevance to Treatment of Parkinson’s Disease:
There is a critical unmet need for therapies that slow or reverse the progression of PD. ShanaRx had identified a signaling pathway whose activation prevents the death of dopamine producing neurons and ameliorate the symptoms associated with dopamine replacement therapy in a rodent PD model. The goal of this project is to quantitatively assess the safety and efficacy of novel drug candidates that activate this signaling cascade in a rodent model of PD. The information will allow identifying a drug candidate that can be advance to clinical trial.
Anticipated Outcome:
ShanaRx will test lead drug candidates that activate the PI3K pathway. In the first am, dose-dependent safety, duration of action, oral availability, and drug distribution will be determined. In the second aim, ShanaRx will determine whether non-toxic doses of the drug candidates are effective in an animal model for PD. Effective and safe drug candidates will be pursued for IND filing and subsequent clinical development.
Final Outcome
Dr. Rosenthal has completed studies examining the therapeutic role of phosphatase inhibitors and found some promising results in the MPTP pre-clinical model though further optimization of pharmacokinetic properties could improve their efficacy.