Promising Outcomes of Original Grant:
We ascertained the associations between GBA mutations and cognitive and motor outcomes in seven large cohorts representing 2,304 patients with PD (including 221 carrying a GBA mutation) and 20,868 longitudinal study visits conducted in England, the Netherlands, France, Canada and the United States. This study found that GBA mutations hasten the longitudinal progression of PD and delineated specific genotype-phenotype correlations.
Objectives for Supplemental Investigation:
The objective of the GBA Meta-Analysis Initiative is to chart a path for success for proof-of-concept clinical trials in patients with GBA-PD. First, we will establish an international consortium of GBA-PD cases and controls. This will serve as a generally useful platform for the rapid testing of molecular markers of target engagement, drug response, and disease modification and for phenotype-to-genotype correlations informative for patient stratification. Second, we will evaluate prioritized candidate sphingolipid biomarkers in CSF and plasma within this consortium both cross-sectionally and longitudinally. Third, we will begin to search for genetic variants modifying the onset of GBA-PD in order to highlight novel targets for tailored therapies.
Importance of This Research for the Development of a New PD Therapy:
This initiative will create a new framework for personalized trials in GBA-PD and begin to develop a trial markers tool kit. It will assemble the tools and information needed for innovative, genetics-inspired, biomarkers-guided GBA-PD Phase II trials. Moreover, genome-wide analysis will highlight novel targets for drugs designed to prevent, delay or slow PD in carriers of a GBA mutation. Finally, the consortium will serve as a versatile platform generally useful for the efficient evaluation of emerging GBA-related biomarker candidates.