Trials of disease-modifying therapies in Parkinson Disease (PD) have been unsuccessful. PD due to monoallelic glucocerebrosidase (GBA1) gene mutations provides a model that is able to overcome many of the hurdles that may have inhibited trial success. GBA1 mutations are the most common genetic factor associated with PD. GBA1 encodes the lysosomal glucocerebrosidase (GCase) enzyme, whose deficiency has been strongly implicated in GBA-related PD as well as a subset of idiopathic PD (IPD). Therefore, evaluating therapeutics in this subgroup of PD addresses an important representative mechanism for PD, decreases the heterogeneity of etiologic mechanism, and provides a known target for intervention. It also lends insight into a subset of IPD. The overarching aim of this proposal is to set the stage for clinical trials in monoallelic-GBA1 PD (GBA-PD) by assessing and validating biomarkers associated with the GCase pathway and GBA-PD. This includes associations between peripheral and central enzymatic activity and lipid levels, and motor and non-motor clinical features. While we have cross-sectional preliminary data, longitudinal assessment of these biomarkers is needed to establish their utility and merit in clinical trials. The incredible resource of the Parkinson Disease Biomarker Program (PDBP) that allows for unprecedented sharing of biospecimen and clinical data enables the proposed work through leveraging our extensive GBA resource. Using combined samples, we propose to characterize focused biochemical measures of the GCase pathway, including central and peripheral biomarker assessments of enzyme, lipid and alpha-synuclein levels and their relation to clinical outcomes and decline. This will not only improve the likelihood of clinical trial success, but will also lead to better understanding of the pathophysiologic mechanisms of this prominent etiology of PD. Specifically, we will: (Aim 1) validate markers determined from our GBA dataset and assess longitudinal change through evaluation of GBA-PD and controls in the unique longitudinal sample from the Harvard Biomarker Study (HBS) and the Parkinson’s Progression Markers Initiative (PPMI) study, will determine the level of association between peripheral and CSF markers from PPMI samples, and identify new epigenomic markers of GBA-PD using our extant samples; (Aim 2) determine association between severity of markers and clinical features of GBA-PD and identify genetic modifiers in extremes of GBA; and (Aim 3) evaluate markers in IPD to discern whether a subset of IPD mimic the higher synuclein load phenotype of GBA-PD, including more cognitive burden and more rapid progression. In sum, GBA-PD is at the forefront of novel approaches to the treatment of PD, potential therapeutic agents are becoming available, and we are at a pivotal stage in the development of trials. Completion of these aims addressing progression and putative pharmacodynamic markers leveraging these special cohorts will not only provide necessary information to foster trial development and success, it will expand our knowledge of the pathophysiology of GBA-PD and subset of IPD as well.
|Effective start/end date||4/1/16 → 8/31/18|
- Icahn School of Medicine at Mount Sinai (0255-1042-4609//U01NS094148)
- National Institute of Neurological Disorders and Stroke (0255-1042-4609//U01NS094148)