Objective: To undertake a repurposing drug screen for Parkinson’s disease (PD) and further investigate the mechanism of action of top hits. To assess, in vivo, the effect of one top hit in a mouse model of PD.
Background: Mitochondrial dysfunction is well characterised in PD, with robust deficits observed in mitochondrial membrane potential (MMP) and cellular ATP. Current treatment options for PD are only able to relieve disease symptoms, with no disease modifying treatments available. Repurposing screens represent an alternative method of finding compounds to treat diseases, with the advantage of already understanding the safety and toxicity profile in humans.
Method: Using patient-derived fibroblasts, a drug repurposing screen was undertaken to assess compound rescue effect on MMP and cellular ATP. Further, in-depth, investigations were undertaken on the top hits, investigating effect on complex I activity and live mitophagy flux in a directly reprogrammed, induced dopaminergic (iDA) neuronal model.
A putative target and mechanism of action was uncovered and investigated via viral knockdown of the target in end stage iDA neurones and CRISPR/Cas9 target knockout iDA neurones.
To assess compound effectiveness, an in vivo study was undertaken. To induce PD, mice were inoculated with Lewy body enriched fractions from human post-mortem brain tissue. Complex I and II activity and target engagement were investigated following daily administrations of our compound.
Results: Following the primary repurposing screen, the top hits were compounds used to treat gout. We observed rescue effects on MMP, ATP, mitophagy and complex I activity. Compound effect on mitophagy was lost following target knockdown or knockout.
Results from the in vivo study confirmed our compound was not toxic and complex I activity was markedly increased in the treatment group. Work is currently ongoing to assess target engagement.
Conclusion: Drug repurposing studies offer an accelerated route for compounds to get to the clinic. We have identified two compounds able to rescue known mitochondrial dysfunction in multiple models of PD and highlighted a possible mechanism by which they may be exerting their effect.
To cite this abstract in AMA style:
R. Hughes, O. Bandmann, L. Ferraiuolo, H. Mortiboys. Repurposing Anti-Gout Medications for the Treatment of Parkinson’s Disease [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/repurposing-anti-gout-medications-for-the-treatment-of-parkinsons-disease/. Accessed May 9, 2025.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/repurposing-anti-gout-medications-for-the-treatment-of-parkinsons-disease/