Wang Shijie, Kelly Kaela, Brotchie Jonathan M, Koprich James B, West Andrew B
Department of Pharmacology and Cancer Biology, Duke Center for Neurodegeneration Research, Duke University, Durham, NC, USA.
Atuka Inc., Toronto, ON, Canada.
NPJ Parkinsons Dis. 2020 Nov 13;6(1):32. doi: 10.1038/s41531-020-00138-7.
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.
过度激活的LRRK2与帕金森病的易感性和病情进展有关。LRRK2抑制的定量测量,尤其是在大脑中的测量,可能对成功开发靶向LRRK2的治疗方法至关重要。在本研究中,将两种不同的可穿透大脑且具有选择性的LRRK2小分子激酶抑制剂(PFE-360和MLi2)口服给予食蟹猴组。将尿液和脑脊液(CSF)中外泌体中拟用的药效学标志物与外周血单核细胞(PBMCs)中已确定的标志物进行比较。LRRK2激酶抑制导致尿液中外泌体-LRRK2蛋白和LRRK2底物pT73-Rab10减少,以及脑脊液中外泌体-LRRK2和自磷酸化的pS1292-LRRK2蛋白减少。我们提出,尿液和脑脊液中用于LRRK2抑制的正交标志物可与血液标志物联合使用,以无创监测靶向LRRK2治疗方法的效力。