Objective/Rationale:
This project focuses on the development of small molecule therapeutics to treat Parkinson’s disease by advancing lead compounds that elevate the abundance of protein chaperones. Protein chaperones are proteins that guide correct protein folding in neurons and other cells and also prevent cell death. Chaperone Therapeutics’ compounds work by stimulating HSF1, a key activator of protein chaperone gene expression, to restore normal protein balance in diseased neurons.
Project Description:
Chaperone Therapeutics is optimizing its lead series compounds for bioavailability, pharmacological suitability and target efficacy. These compounds were identified using Chaperone’s proprietary screening technology and shown to be active in cellular assays as well as in pharmaceutical suitability models. Prior to testing these compounds in pre-clinical models of Parkinson’s disease, they must be shown to elevate the levels of protein chaperones in vivo. To this end we will test lead compounds in cells lacking HSF1 to establish their dependence on HSF1 and in pre-clinical pharmacokinetic models using by direct injection into the cranial cavity. Ultimately, the primary goal of the project outlined here is to produce therapeutics for the treatment of Parkinson’s disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Recent evidence in vitro and in vivo strongly supports the hypothesis that protein chaperones act both independently and cooperatively to ameliorate biochemical hallmarks and symptoms of Parkinson’s disease. For example, in pre-clinical models of alpha-synuclein toxicity, elevated expression of protein chaperones significantly suppresses protein aggregation, increases protein solubility and ameliorates neuronal loss. Given the potential therapeutic role of elevated protein chaperone levels in ameliorating alpha-synuclein aggregation and enhancing neuronal survival, small molecule-mediated activation of human HSF1 is a promising avenue for therapeutic intervention in Parkinson’s disease.
Anticipated Outcome:
This work will test the efficacy of Chaperone Therapeutics small molecules in elevating protein chaperone levels in cell culture and in pre-clinical models. Successful completion of this project will yield a small molecule drug lead against a new and exciting target for the treatment of Parkinson’s disease.