Differential Inhibition of LRRK2 in Parkinson's Disease Patient Blood by a G2019S Selective LRRK2 Inhibitor

BACKGROUND: A common genetic mutation that causes Parkinson's disease (PD) is the G2019S LRRK2 mutation.

A precision medicine approach that selectively blocks only excess kinase activity of the mutant allele could yield a safe and effective treatment for G2019S LRRK2 PD.

OBJECTIVE: To determine the activity of a G2019S mutant selective leucine‐rich repeat kinase 2 (LRRK2) kinase inhibitor as compared to a nonselective inhibitor in blood of subjects with genetic and idiopathic PD on two LRRK2 biomarkers, pSer935 LRRK2 and pThr73 Rab10.

METHODS: Blood was collected from 13 subjects with or without a G2019S LRRK2 mutation with PD and one healthy control.

Peripheral blood mononuclear cells were treated ex vivo with a novel G2019S LRRK2 inhibitor (EB‐42168) or the nonselective inhibitor MLi‐2.

Quantitative western immunoblot analyses were performed.

RESULTS: EB‐42168 was 100 times more selective for G2019S LRRK2 when compared to wild‐type (WT) LRRK2.

Concentrations that inhibited phosphorylation of pSer935 LRRK2 by 90% in homozygous G2019S LRRK2 patients, inhibited pSer935 LRRK2 by 36% in heterozygous patients, and by only 5% in patients carrying only the WT allele.

Similar selectivity was seen for pThr73 Rab10.

MLi‐2 showed an equivalent level of inhibition across all genotypes.

CONCLUSIONS: These findings demonstrate that EB‐42168, a G2019S LRRK2 selective inhibitor, lowers mutant G2019S LRRK2 phosphorylated biomarkers while simultaneously sparing WT LRRK2.

Selective targeting of G2019S LRRK2 with a small molecule lays the foundation for a precision medicine treatment of G2019S LRRK2 PD.

© 2021 ESCAPE Bio, Inc.

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society