Promising Outcomes of Original Grant:
Funding from The Michael J. Fox Foundation (MJFF) has facilitated the rapid screening of over 370,000 compounds of chemicals that prevent alpha-synuclein (protein that clumps in the brains of those with Parkinson's) accumulation. At the end of the original grant period, we identified three chemical compounds that could specifically reduce alpha-synuclein accumulation.
Objectives for Supplemental Investigation:
Following completion of the aims of our previous study, we are in a strong position to pursue identified hits as well as continue to assay (test) and characterize hits. With this supplemental funding, we will design, synthesize and test the hits identified in the original grant. The McLean lab is well-placed to continue to screen optimized compounds using biochemical and cell-based assays. Compounds that show improved potency and selectivity will be advanced for further optimization at the Sanford Burnham Prebys Medical Discovery Institute.
Importance of This Research for the Development of a New PD Therapy:
There are currently no therapeutic interventions that halt or reverse the progression of Parkinson's disease (PD). The market for PD therapeutics is small compared to diseases with a much higher incidence (e.g., cancer or heart disease) and, as a result, there is little incentive for the development of significant PD drug discovery programs within the pharmaceutical industry. Therefore, there is a great need to de-risk novel therapeutic targets and strategies for the treatment of PD. Our MJFF-funded approach has identified chemical compounds that target the stage of alpha-synuclein fibrillation (clumping of misfolded proteins), where soluble forms of alpha-synuclein could potentially rescue alpha-synuclein-induced cell death, impact disease progression and, thus, become potential candidate compounds for disease-modifying therapies.
An overarching aim of our studies is to develop compounds that prevent clumping of the protein alpha-synuclein, a process that characterizes Parkinson's disease (PD). The purpose of the supplemental study was to further optimize select therapeutic compounds developed earlier. Despite considerable efforts, we have not been able to improve existing compounds or identify a more potent compound that blocks alpha-synuclein clumping. Nonetheless, we have identified a compound that could potentially become a tool for confirming the therapeutic effect of decreasing alpha-synuclein clumping in pre-clinical models. Ongoing and future studies will focus on improving this compound.