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

Content Provider	Europe PMC
Author	Bright, Jessica M. Carlisle, Holly J. Toda, Alyssa M. A. Murphy, Molly Molitor, Tyler P. Wren, Paul Andruska, Kristin M. Liu, Enchi Barlow, Carrolee
Abstract	ABSTRACTBackgroundA 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.ObjectiveTo 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.MethodsBlood 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.ResultsEB‐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.ConclusionsThese 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
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC8248170&blobtype=pdf
Page Count	10
ISSN	08853185
Journal	Movement Disorders [Mov Disord]
Volume Number	36
DOI	10.1002/mds.28490
PubMed Central reference number	PMC8248170
Issue Number	6
PubMed reference number	33836114
e-ISSN	15318257
Language	English
Publisher	John Wiley & Sons, Inc.
Publisher Date	2021-02-11
Publisher Place	Hoboken, USA
Access Restriction	Open
Rights License	This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2021 ESCAPE Bio, Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Subject Keyword	pharmacodynamic biomarker Parkinson's disease G2019S LRRK2 peripheral blood mononuclear cells
Content Type	Text
Resource Type	Article
Subject	Neurology Neurology (clinical)