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Drugs

, Volume 79, Issue 10, pp 1037–1051 | Cite as

Recent Developments in LRRK2-Targeted Therapy for Parkinson’s Disease

  • Ye Zhao
  • Nicolas DzamkoEmail author
Leading Article

Abstract

Kinase activating missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenically linked to neurodegenerative Parkinson’s disease (PD). Over the past decade, substantial effort has been devoted to the development of potent and selective small molecule inhibitors of LRRK2, as well as their preclinical testing across different Parkinson’s disease models. This review outlines the genetic and biochemical evidence that pathogenic missense mutations increase LRRK2 kinase activity, which in turn provides the rationale for the development of small molecule inhibitors as potential PD therapeutics. An overview of progress in the development of LRRK2 inhibitors is provided, which in particular indicates that highly selective and potent compounds capable of clinical utility have been developed. We outline evidence from rodent- and human-induced pluripotent stem cell models that support a pathogenic role for LRRK2 kinase activity, and review the substantial experiments aimed at evaluating the safety of LRRK2 inhibitors. We address challenges still to overcome in the translational therapeutic pipeline, including biomarker development and clinical trial strategies, and finally outline the potential utility of LRRK2 inhibitors for other genetic forms of PD and ultimately sporadic PD. Collective evidence supports the ongoing clinical translation of LRRK2 inhibitors as a therapeutic intervention for PD is greatly needed.

Notes

Compliance with Ethical Standards

Funding

No funding was specifically received for the publication of this review

Conflict of interest

ND receives funding for Parkinson’s disease research, including on LRRK2, from the National Health and Medical Research Council (NHMRC) (#1103757), the Michael J Fox Foundation for Parkinson’s disease research (MJFF), the Shake It Up Australia Foundation and the University of Sydney. In the past 12 months ND has received travel support from Denali Therapeutics, Neuropore therapies and MJFF and received payments for Grant reviews from the NHMRC and IRC. ND is a co-inventor and has received royalties from a patent on the use of LRRK2 phosphorylation sites as pharmacodynamic biomarkers (WO2011131980A1). YZ has no conflicts of interest to declare.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Brain and Mind Centre, Central Clinical SchoolUniversity of SydneyCamperdownAustralia

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