Differential Inhibition of LRRK2 in Parkinson's Disease Patient Blood by a G2019S Selective LRRK2 Inhibitor. Issue 6 (11th February 2021)

• Record Type: Journal Article
• Authors: Bright, Jessica M.; Carlisle, Holly J.; Toda, Alyssa M. A.; Murphy, Molly; Molitor, Tyler P.; Wren, Paul; Andruska, Kristin M.; Liu, Enchi; Barlow, Carrolee
• Is Part Of: Movement disorders. Volume 36:Issue 6(2021)
• Page Start: 1362
• Page End: 1371
• Publication Date: 2021-02-11
• Subjects: pharmacodynamic -- biomarker -- Parkinson's disease -- G2019S LRRK2 -- peripheral blood mononuclear cells; Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.28490
• Languages: English
• ISSNs: 0885-3185

Abstract

ABSTRACT: 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