Abstract
Hyper-activated LRRK2 is linked to Parkinson’s disease susceptibility and progression. Quantitative measures of LRRK2 inhibition, especially in the brain, maybe critical in the development of successful LRRK2-targeting therapeutics. In this study, two different brain-penetrant and selective LRRK2 small-molecule kinase inhibitors (PFE-360 and MLi2) were orally administered to groups of cynomolgus macaques. Proposed pharmacodynamic markers in exosomes from urine and cerebrospinal fluid (CSF) were compared to established markers in peripheral blood mononuclear cells (PBMCs). LRRK2 kinase inhibition led to reductions in exosome-LRRK2 protein and the LRRK2-substrate pT73-Rab10 in urine, as well as reduced exosome-LRRK2 and autophosphorylated pS1292-LRRK2 protein in CSF. We propose orthogonal markers for LRRK2 inhibition in urine and CSF can be used in combination with blood markers to non-invasively monitor the potency of LRRK2-targeting therapeutics.
Highlights
Leucine-rich repeat kinase 2 (LRRK2) small-molecule kinase inhibitors and anti-sense oligonucleotides have demonstrated neuroprotective efficacy in some models of Parkinson’s disease (PD) and represent a promising novel class of disease-modifying therapeutics for neurodegeneration[1,2,3]
This study identifies efficacious target engagement measures for LRRK2 kinase inhibition in exosomes isolated from urine and cerebrospinal fluid (CSF) of non-human primates using two distinct small-molecules (PFE360 and MLi2)
Our results build on observations comparing pS935-LRRK2 peripheral blood mononuclear cells (PBMCs) and brain tissue lysate measurements in treated macaques[18], as well as pS1292-LRRK2 levels measured in treated mice[19]
Summary
Leucine-rich repeat kinase 2 (LRRK2) small-molecule kinase inhibitors and anti-sense oligonucleotides have demonstrated neuroprotective efficacy in some models of Parkinson’s disease (PD) and represent a promising novel class of disease-modifying therapeutics for neurodegeneration[1,2,3]. Reliable measures of LRRK2 expression and enzymatic inhibition may assist in the identification of the most efficacious LRRK2-targeting therapies, in early phase clinical trials[6,7]. LRRK2 exists as a phospho-protein in all cells and tissues so-far evaluated[7,8], with an N-terminal cluster of phosphorylated residues sensitive to LRRK2 kinase inhibition[9,10,11]. The more recently discovered LRRK2-autophosphorylation residue pS1292LRRK2 localizes to the C-terminal region of the LRRK2 leucine-rich repeat (LRR) domain, nearby the Rab-like ROC domain[12,13,14]. LRRK2 kinase activity regulates levels of pT73-Rab[10], as observed in inhibitor treatments of immune cells that express high levels of LRRK2 protein (e.g., monocytes, neutrophils)[15].
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