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Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease.

Publication ,  Journal Article
West, AB
Published in: Exp Neurol
December 2017

In the translation of discoveries from the laboratory to the clinic, the track record in developing disease-modifying therapies in neurodegenerative disease is poor. A carefully designed development pipeline built from discoveries in both pre-clinical models and patient populations is necessary to optimize the chances for success. Genetic variation in the leucine-rich repeat kinase two gene (LRRK2) is linked to Parkinson disease (PD) susceptibility. Pathogenic mutations, particularly those in the LRRK2 GTPase (Roc) and COR domains, increase LRRK2 kinase activities in cells and tissues. In some PD models, small molecule LRRK2 kinase inhibitors that block these activities also provide neuroprotection. Herein, the genetic and biochemical evidence that supports the involvement of LRRK2 kinase activity in PD susceptibility is reviewed. Issues related to the definition of a therapeutic window for LRRK2 inhibition and the safety of chronic dosing are discussed. Finally, recommendations are given for a biomarker-guided initial entry of LRRK2 kinase inhibitors in PD patients. Four key areas must be considered for achieving neuroprotection with LRRK2 kinase inhibitors in PD: 1) identification of patient populations most likely to benefit from LRRK2 kinase inhibitors, 2) prioritization of superior LRRK2 small molecule inhibitors based on open disclosures of drug performance, 3) incorporation of biomarkers and empirical measures of LRRK2 kinase inhibition in clinical trials, and 4) utilization of appropriate efficacy measures guided in part by rigorous pre-clinical modeling. Meticulous and rational development decisions can potentially prevent incredibly costly errors and provide the best chances for LRRK2 inhibitors to slow the progression of PD.

Duke Scholars

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Published In

Exp Neurol

DOI

EISSN

1090-2430

Publication Date

December 2017

Volume

298

Issue

Pt B

Start / End Page

236 / 245

Location

United States

Related Subject Headings

  • Protein Serine-Threonine Kinases
  • Protein Kinase Inhibitors
  • Parkinson Disease
  • Neuroprotection
  • Neurology & Neurosurgery
  • Models, Biological
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Humans
  • Animals
  • 5202 Biological psychology
 

Citation

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MLA
NLM
West, A. B. (2017). Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Exp Neurol, 298(Pt B), 236–245. https://doi.org/10.1016/j.expneurol.2017.07.019
West, Andrew B. “Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease.Exp Neurol 298, no. Pt B (December 2017): 236–45. https://doi.org/10.1016/j.expneurol.2017.07.019.
West, Andrew B. “Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease.Exp Neurol, vol. 298, no. Pt B, Dec. 2017, pp. 236–45. Pubmed, doi:10.1016/j.expneurol.2017.07.019.
West AB. Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Exp Neurol. 2017 Dec;298(Pt B):236–245.
Journal cover image

Published In

Exp Neurol

DOI

EISSN

1090-2430

Publication Date

December 2017

Volume

298

Issue

Pt B

Start / End Page

236 / 245

Location

United States

Related Subject Headings

  • Protein Serine-Threonine Kinases
  • Protein Kinase Inhibitors
  • Parkinson Disease
  • Neuroprotection
  • Neurology & Neurosurgery
  • Models, Biological
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Humans
  • Animals
  • 5202 Biological psychology