TABLE 6

Target familial PD genes that contribute to α-synuclein toxicity – LRRK2

AgentSponsorMechanism of ActionType of TherapyPhase of DevelopmentStatus/Findings
DNL151Denali TherapeuticsInhibit LRRK2 kinase activitySmall moleculePhase 1NCT04056689: completed, results pending
NCT04557800: recruiting
DNL201Denali TherapeuticsInhibit LRRK2 kinase activitySmall moleculePhase 1NCT03710707 and NCT04551534: completed, results pending
ION859/BIIB094BiogenReduce LRRK2 protein levelsASOPhase 1NCT03976349: recruiting
MLi-2MerckDecreases LRRK2 kinase activitySmall moleculePreclinicalWas not protective in the MitoPark mouse model (Fell et al., 2015)
LRRK2-IN-1Blocks LRRK2 kinase activitySmall moleculePreclinicalNot yet tested in PD model systems but shown to block LRRK2 kinase activity in cell culture (Deng et al., 2011)
PF-06447475PfizerBlocks LRRK2 kinase activitySmall moleculePreclinicalProtects against dopaminergic cell loss in AAV-α-Syn rats (Daher et al., 2015)
JH-II-127Inhibits LRRK2 kinase activitySmall moleculePreclinicalNot yet tested in PD model systems but found to inhibit LRRK2 kinase activity in the mouse brain after oral treatment (Hatcher et al., 2015)
miRNA-205Downregulates LRRK2 expressionNucleic acidPreclinicalProtects against neurite outgrowth deficits in LRRK2 R1441G primary neurons (Cho et al., 2013)