What to Test in Parkinson Disease Prevention Trials? Repurposed, Low-Risk, and Gene-Targeted Drugs

Abstract

Despite the sound epidemiologic and basic science rationales underpinning numerous "disease modification" trials in manifest Parkinson disease (PD), none has convincingly demonstrated that a treatment slows progression. Rapidly expanding knowledge of the genetic determinants and prodromal features of PD now allows realistic planning of prevention trials with initiation of putatively neuroprotective therapies earlier in the disease. In this article, we outline the principles of drug selection for PD prevention trials, focused on proof-of-concept opportunities that will help establish a methodological foundation for this fledgling field. We describe prototypical, relatively low-risk drug candidates for such trials (e.g., albuterol, ambroxol, caffeine, ibuprofen), tailored to specific at-risk populations ranging from pathogenic LRRK2 or GBA gene variant carriers to those defined by prodromal PD and α-synucleinopathy. Finally, we review gene-targeted approaches currently in development targeting clinically manifest PD for their potential in future prevention trials.

Figure. Drug Candidates and Their Rationales for PD Prevention Trials

Partial listing of plausibly neuroprotective potential therapeutic agents, organized by their relative safety risk into low and high, which corresponds to their status as repurposable drugs (for which there are extensive safety data) and novel drugs (for which there is little or no human safety data). Proximal mechanisms of putative neuroprotective action are listed, along with the at-risk population most rationally targeted at this point based on multiple lines of evidence (broken out to human genetic, epidemiologic, and preclinical models). The number of + signs indicates authors' subjective impression of the strength of evidence in a given category, with brackets reflecting more indirect evidence. ✔ indicates supportive evidence in toxin and/or genetic preclinical models of PD. Citations for most recent study (see text for reference) or associated clinical trial associated with proposed agents (a = ACTRN12620000560998, b = NCT03905811, c = NCT04386317, d = NCT04777331, e = NCT02606682, f = NCT04685265, g = NCT04483479, h = NCT03655236, i = NCT04127578, j = Trial NL7061 [NTR7299]]). αSyn = alpha-synuclein; ASO = antisense oligonucleotide; COX = cyclooxygenase; ER = extended release; GCase = glucocerebrosidase; NSAID = nonsteroidal anti-inflammatory drug; PD = Parkinson disease; PPAR-γ = peroxisome proliferator–activated receptor gamma; ProPD = prodromal PD; RBD = REM sleep behavior disorder.