Drug repurposing strategies of relevance for Parkinson's disease

Abstract

Parkinson's disease is a highly disabling, progressive neurodegenerative disease that manifests as a mix of motor and non-motor signs. Although we are equipped with some symptomatic treatments, especially for the motor signs of the disease, there are still no established disease-modifying drugs so the disease progresses unchecked. Standard drug discovery programs for disease-modifying therapies have provided key insights into the pathogenesis of Parkinson's disease but, of the many positive candidates identified in pre-clinical studies, none has yet translated into a successful clinically efficacious drug. Given the huge cost of drug discovery programs, it is not surprising that much attention has turned toward repurposing strategies. The trialing of an established therapeutic has the advantage of bypassing the need for preclinical safety testing and formulation optimization, thereby cutting both time and costs involved in getting a treatment to the clinic. Additional reduced failure rates for repurposed drugs are also a potential bonus. Many different strategies for drug repurposing are open to researchers in the Parkinson's disease field. Some of these have already proven effective in identifying suitable drugs for clinical trials, lending support to such approaches. In this review, we present a summary of the different strategies for drug repurposing, from large-scale epidemiological correlation analysis through to single-gene transcriptional approaches. We provide examples of past or ongoing studies adopting each strategy, where these exist. For strategies that have yet to be applied to Parkinson's disease, their utility is illustrated using examples taken from other disorders.

Keywords: clinical observation; epidemiological correlation; genome-wide association studies; target identification; transcriptional profiling.

FIGURE 1

Schematic representation of the repurposing journey of the glucagon‐like‐peptide‐1 (GLP‐1) receptor agonist, exenatide in Parkinson's disease (PD). Type II diabetes mellitus (T2DM) was recognised as a potential risk factor for PD. Independent scrutiny of records from the UK Clinical Practice Research Datalink (CPRD) database and the Norwegian Prescription (NorP) database reported a consistent reduction in the incidence of PD in T2DM patients prescribed glitazones compared to those given treatments such as sulphonylureas or metformin. Subsequent interrogation of The Health Improvement Network (THIN) database revealed the incidence of newly diagnosed PD in T2DM patients receiving glitazones was not different to that in a matched non‐diabetic control group. However, those treated with GLP‐1 receptor agonists such as exenatide showed reduced incidence of PD. In pre‐clinical studies, exenatide provided neuroprotection in a GLP‐1 receptor‐dependent manner. Proof‐of concept and tolerability of exenatide was established via open label trial, with a follow‐up randomised placebo‐controlled trial revealing clinical improvement in some motor scores. Phase III multi‐centre clinical trials are now underway to assess the neuroprotective effects of exenatide in PD patients without co‐morbid T2DM (ClinicalTrials.gov Identifier: NCT04232969). Abbreviations: 6‐OHDA, 6‐hydroxydopamine; MPTP, 1‐methyl‐4‐phenyl, 1,2,3,6‐tetrahyropyridine. Numbers in parentheses indicate citations.