Kuldip D. Dave1, Adria K. Martig1, Terina N. Martinez1, Lee J. Pellegrino2, Leo B. Dungan2, Rick Hamler2, Sean W. Clark2, Peter D. Buckett3, Yi Chen3, Weisong Shan3, Warren D. Hirst3, Michael Sasner4, Mark Herberth5, Robert Switzer6, Todd B. Sherer1 and Brian K. Fiske1
1The Michael J. Fox Foundation, New York NY; 2Amicus Therapeutics, Cranbury, NJ; 3Pfizer, Boston, MA; 4The Jackson Laboratory, Bar Harbor, ME; 5WIL Research, Ashland, OH; 6NeuroScience Associates, Knoxville, TN.
Heterozygous mutations in the GBA1 gene, which encodes for lysosomal glucocerebrosidase (GCase), have been identified as the most common genetic risk factor for Parkinson's disease (PD). Decreased GCase activity has been reported in PD patients, in both genetic as well as in sporadic cases and emerging experimental evidence suggests a correlation between this decreased activity and accumulation of alpha-synuclein (aSyn). These strong genetic and pathological links make GCase an attractive target for PD drug development. As such, The Michael J. Fox Foundation (MJFF) has made robust investments to address key questions to effectively translate GCase therapeutically for PD patients. First, are GBA1 mutations relevant to sporadic Parkinson's and could a therapeutic directed against GBA1-mediated Parkinson's be efficacious for general PD population? To address this challenge, MJFF has funded biomarker studies in samples from sporadic patients to determine how GCase levels/activity and lipid substrates relate to aSyn burden and disease severity. Also, MJFF initiated recruitment of 250 GBA1 (125 affected and 125 unaffected) mutation carriers to the Parkinson's Progression Markers Initiative to identify GBA1-related biomarkers and inform our understanding of the natural history of PD. Second, the hypothesis that reduced GCase activity is causative of PD via aSyn accumulation needs to be confirmed. To address this issue, MJFF has funded generation of animal models and tools that would aid in studying the reciprocal relationship between GCase and aSyn, and for testing efficacy. The GBA1 D409V knock‑in mouse model developed in collaboration with MJFF's Industry Tools Consortium shows a gene dose-dependent reduction in GCase activity and a corresponding increase in substrate accumulation. MJFF is further characterizing this model by crossing it with an aSyn transgenic mouse to determine if loss of GBA1 function affects aSyn induced pathology and related phenotypes. Third, it remains unclear what is the most optimal approach to target GCase therapeutically. To this end, MJFF has funded diverse programs to increase GCase activity to possibly slow disease progression and "reverse" synuclein-related pathological manifestations of the disease. This includes therapeutic programs which increase stabilization and lysosomal translocation of GCase or direct activation of GCase, which would increase the levels of functional enzyme in lysosomes. MJFF's vision is to apply a holistic strategy to address research and therapeutic chalemenges to enable accelerated development of GBA1-targeting therapeutics and optimally informed clinical trials.