Drug repurposing for disease-modifying effects in multiple system atrophy

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder lacking any proven disease-modifying therapy. Drug repurposing offers a strategy to accelerate the development of treatments by utilizing agents originally approved for other indications. This review summarizes repurposed drugs investigated as disease-modifying therapies for MSA, spanning preclinical in vitro and animal studies and clinical trials. We focus on agents targeting key pathogenic mechanisms in MSA—including α-synuclein aggregation (e.g., sirolimus/rapamycin, rifampicin, lithium, nilotinib, epigallocatechin gallate), neuroinflammation (e.g., minocycline, intravenous immunoglobulin), mitochondrial dysfunction and excitotoxicity (e.g., ubiquinol, rasagiline, safinamide, riluzole), and impaired neurotrophic support (e.g., fluoxetine/selective serotonin reuptake inhibitors, insulin, exendin-4). For each, we discuss mechanisms of action, experimental model outcomes, and clinical trial results. While numerous repurposed agents showed promise in MSA models, most failed to demonstrate significant disease-slowing effects in clinical trials. However, ubiquinol has recently emerged as a notable exception, with a Phase 2 randomized controlled trial showing a significant reduction in motor progression compared to placebo—marking the first placebo-controlled evidence of disease modification in MSA. Limitations such as small sample sizes, late-stage patient enrollment, and tolerability issues (e.g., with lithium) have hampered past trials. Nonetheless, ongoing studies and emerging approaches such as combination therapies hold promise. Continued exploration of repurposed therapies, along with improved trial design and biomarker development, is warranted to finally achieve a disease-modifying treatment for MSA.