Drug Repurposing for Parkinson's Disease: A Large-Scale Multi-Cohort Study

Summary

Background Progress in Parkinson’s disease (PD) is hampered by two critical obstacles: the lack of disease-modifying drugs and the difficulty of identify individuals at early, prodromal disease stages for clinical trials.

Methods We conducted a retrospective, multi-cohort study using data from the Mass General Brigham (MGB) Biobank for discovery and the Accelerating Medicines Partnership Parkinson’s Disease (AMP-PD) program for replication. Logistic regression was used to estimate the associations between drug exposure and the subsequent risk of PD. Sensitivity analyses addressed dose effects and reverse causality. Longitudinal changes in cognitive and motor function were analyzed using linear mixed-effects models. We also mapped drug target genes to cell types to explore potential therapeutic targets for PD.

Findings We included a total of 44,388 individuals in the discovery cohort (15,032 cases and 29,356 controls) and 4010 individuals in the validation cohort (2,351 cases and 1659 controls). In this study, 18 drugs were replicated, with five associated with reduced PD risk and 13 with increased risk. Notably, salbutamol (discovery: 0.84, 95% CI 0.80–0.88; replication: 0.70, 95% CI 0.49–0.99) and losartan prescriptions (discovery: 0.90, 95% CI 0.84–0.96; replication: 0.67, 95% CI 0.51–0.88) were associated with reduced risk of PD with lag times of 0-5 years. Moreover, in longitudinal analyses of patients with PD over 10 years, cognitive function over time was improved in patients taking losartan compared to patients not on this drug. Solifenacin was associated with less severe motor impairment. Furthermore, eight differentially expressed drug target genes were identified in PD, including significant downregulation of CFTR in oligodendrocytes and NR3C2 in microglia.

Interpretation Salbutamol and losartan show significant associations with PD risk and can be further tested mechanistically and clinically. Drugs for non-motor symptoms show promise for identifying putative prodromal PD at scale using data science. CFTR and NR3C2 represent compelling druggable target candidates for therapeutic development in PD and warrant further functional validation.

Funding The Michael J. Fox Foundation for Parkinson’s Research (MJFF) and the Aligning Science Across Parkinson’s (ASAP) initiative.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This research was funded in whole or in part by Aligning Science Across Parkinson's [ASAP-000301] and [ASAP-000529] through the Michael J. Fox Foundation for Parkinson's Research (MJFF).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB of Mass General Brigham Human Research Committee gave ethical approval for this work involving the use of de-identified electronic health record data from the MGB Biobank. Ethics committee/IRB of the AMP-PD consortium approved the use of de-identified health data from the PPMI and PDBP cohorts for research purposes under data use agreements. Single-cell RNA sequencing data analyzed in this study were obtained from publicly available datasets published in peer-reviewed journals. These datasets were already de-identified and approved for public reuse by their original ethics boards, and no additional ethical approval was required for their use in this study.

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