Drug Repositioning Strategies to Accelerate Therapeutic Development for Rare Diseases A Narrative Review

An Overview of Computational, Phenotypic, and Regulatory Approaches

Resumo

Rare diseases defined as conditions affecting fewer than 1 in 2,000 individuals—collectively affect approximately 300 million people worldwide, yet more than 90% remain without approved therapy. Conventional drug development, with its decade-long timelines, multibillion-dollar costs, and failure rates exceeding 90%, is poorly suited to this population. We conducted a narrative review of the peer-reviewed literature (2019–2025) on drug repositioning for rare diseases, focusing on computational, experimental, clinical/observational, and integrative strategies, regulatory pathways, and illustrative case studies. Sources were identified through targeted searches of PubMed and Google Scholar using combinations of the terms drug repurposing, drug repositioning, rare disease, and orphan drug, supplemented by hand-searching of reference lists. Drug repositioning offers substantial reductions in cost and development time relative to de novo drug discovery by leveraging established safety and pharmacokinetic data. We synthesize evidence across four methodological strategies and illustrate the field's potential and limitations through case studies including thalidomide, sildenafil, and sirolimus. Realizing the full promise of drug repositioning for rare diseases will require stronger data-sharing infrastructure, clearer regulatory pathways for repurposed indications, and sustained collaboration among academia, patient organizations, and industry.