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Editorial
. 2023 Mar;38(3):361-365.
doi: 10.1002/mds.29343.

LRRK2-Targeting Therapies March Through the Valley of Death

Andrew B West  1 , Michael A Schwarzschild  2
Affiliations
Editorial

LRRK2-Targeting Therapies March Through the Valley of Death

Andrew B West et al. Mov Disord. 2023 Mar.
No abstract available

Keywords: clinical trials; leucine-rich repeat kinase 2; neuroprotectants.

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Conflict of interest statement

A.B.W. has received federal research grant support from NIH NINDS R01 NS064934, P50 NS108675 and R33 NS097643, and has served as a member of the Michael J. Fox Executive Foundation (MJFF) Scientific Advisory Board, a paid consultant for EscapeBio Inc., and has received research grants from Biogen Inc. and EscapeBio, Inc, as well as MJFF, ASAP foundation, Parkinson’s Foundation, and National Institutes of Health. A.B.W. is part owner of a series of LRRK2 kinase inhibitor (WO 2013166276) and part owner of induced-pluripotent stem cell lines of early-onset PD distributed by Cedars Sinai. M.A.S. receives consultancy payment from the Parkinson Study Group (PSG) for service on the Global S teering Committee of LIGHTHOUSE and LUMA for studies of BIIB122. He also received advisory board, data monitoring committee, steering committee, and/or travel payments in the past 3 years from Denali Therapeutics, Eli Lilly & Co, the PSG (for advising Bial, Biogen, Partner Therapeutics, and UCB), Cure Parkinson’s, World Parkinson Congress, Parkinson’s Foundation, MJFF, Sutter Health, Northwestern University, and National Institutes of Health.

Figures

Figure 1.
Figure 1.. Hypothesized genetic and biomarker-based enrichments may maximize the potential for LRRK2-targeting therapies in PD.
Green coloration indicates the PD population that might be prioritized for enrollment in LRRK2-targeted therapies, whereas red coloration indicates PD cases that might be lower priority initially. *rs76904798 is linked to PD in Caucasian populations but not East Asians, and **G2385R is linked to PD in East Asians and not Caucasians. The N551K-R1398H haplotype might be protective from PD and highlight cases where LRRK2 may not play a major role in risk or progression. Putative LRRK2-activity biomarkers might include measures of autophosphorylated LRRK2 (pS1292-LRRK2) or Rab protein phosphorylation (e.g., pT73-Rab10).
See this image and copyright information in PMC

Comment on

  • LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease.
    Jennings D, Huntwork-Rodriguez S, Vissers MFJM, Daryani VM, Diaz D, Goo MS, Chen JJ, Maciuca R, Fraser K, Mabrouk OS, van de Wetering de Rooij J, Heuberger JAAC, Groeneveld GJ, Borin MT, Cruz-Herranz A, Graham D, Scearce-Levie K, De Vicente J, Henry AG, Chin P, Ho C, Troyer MD. Jennings D, et al. Mov Disord. 2023 Mar;38(3):386-398. doi: 10.1002/mds.29297. Epub 2023 Feb 18. Mov Disord. 2023. PMID: 36807624 Clinical Trial.

References

    1. Jennings et al. (Placeholder) LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson’s Disease. In press Movement Disorders 2023. - PubMed
    1. Butler D Translational research: crossing the valley of death. Nature 2008;453(7197):840–842. - PubMed
    1. Jennings D, Huntwork-Rodriguez S, Henry AG, et al. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease. Sci Transl Med 2022;14(648):eabj2658. - PubMed
    1. Finkbeiner S. Bridging the Valley of Death of therapeutics for neurodegeneration. Nat Med 2010;16(11):1227–1232. - PubMed
    1. Fillit H Pfizer Ends Its Neuroscience Program—What Does it Mean For Alzheimer’s? 2018.

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