Target familial PD genes that contribute to α-synuclein toxicity—GCase

AgentSponsorMechanism of ActionType of TherapyPhase of DevelopmentStatus/Findings
AmbroxolLawson Health Research Institute, U Western OntarioIncreases GCase activity by binding the active siteSmall moleculePhase 2NCT02914366: recruiting
LTI-291Lysosomal TherapeuticsAllosteric modulator that enhances GCase activitySmall moleculePhase 1NTR6598 and NTR6705 (Dutch trial registry): good safety and tolerability
S-181Increases GCase activitySmall moleculePreclinicalDecreases insoluble α-Syn in the brain of Gba1 mutant mice (Burbulla et al., 2019)
IsofagomineAmicus therapeuticsGCase chaperone that increases its stabilitySmall moleculePreclinical in PD, phase 2 in Gaucher diseaseNCT00446550 and NCT00433147: good safety and tolerability
NCGC758 and NCGC607GCase chaperones that translocate GCase to the lysosome and increases GCase activitySmall moleculesPreclinicalEnhance clearance of α-Syn in iPSC-derived human dopaminergic neurons (Aflaki et al., 2016; Mazzulli et al., 2016b)
PR001Prevail Therapeutics/Eli Lilly & CompanyAAV9-mediated GBA1 replacementGene therapyPhase 1/2aNCT04127578: recruiting
VenglustatGenzymeGlucosylceramide synthase inhibitorSmall moleculePhase 2NCT02906020: active, not recruiting, but failed to meet primary endpoints
GZ667161Glucosylceramide synthase inhibitorSmall moleculePreclinicalDecreases α-Syn accumulation and protect against cognitive deficits in GbaD409V/D409V and A53T–α-Syn overexpressing mice (Sardi et al., 2017)
ESB-1609Escape BioS1P5 receptor agonist, leading to rescue of GCase activity in patients with GBA-PDSmall moleculePhase 1
FingolimodS1P receptor agonistSmall moleculePreclinical in PD but FDA-approved for MSDecreases α-Syn accumulation in A53T–α-Syn overexpressing mice and GM2+/− mice and protects against motor deficits in GM2+/− mice and rotenone challenged mice (Ren et al., 2017; Vidal-Martinez et al., 2016, 2019); decreases markers of inflammation in the striatum, protects against neuronal loss in the SN, and protects against motor deficits in the MPTP mouse (Pépin et al., 2020)