Drug repurposing (or repositioning) is the application of previously identified drugs or compounds to treat new indications. In general, repurposing forms an accelerated approach for finding new therapies. Repurposing may comprise new therapeutic use for marketed drugs, for drug candidates that are currently in clinical development, or for drugs that have been abandoned/failed for a particular indication due to efficacy problems. Other aspects include the development of different formulations or drug delivery systems for an approved drug, or establishing new combinations of individual drugs.
Identifying compounds for repurposing requires a broad variety of approaches including mining of existing scientific databases, in silico bio- and cheminformatics strategies to link drug to disease, in vitro (high-throughput) drug screenings, in vivo experiments, toxicity and pharmacokinetic/dynamic studies. Formulation in drug delivery systems may be used to reduce adverse events.
The International Rare Diseases Research Consortium (IRDiRC) set as main goal for 2027 that 1000 new therapies for rare diseases will be approved. One of the levers to achieve this goal includes the repurposing of already existing and marketed drugs. An example suitable for repurposing is Autosomal Dominant Polycystic Kidney Disease (ADPKD). ADPKD is an inherited kidney disorder with a prevalence of 3:10.000 characterised by the development of renal cysts, slowly progressing towards end-stage renal disease at the age of 50-60 years. Current therapies are directed towards limiting morbidity and mortality from complications of ADPKD . Therefore, there is a need for drugs that specifically target the formation and growth of cysts to slow down or halt disease progression. Given the complexity of altered signalling in cyst-lining epithelium, a phenotypic testing approach to repurpose drugs that are on the market for other diseases is the most logical approach to swiftly bring new therapies to the clinic.
In this context, DRUGtrain (DRUG repurposing and discovery multidisciplinary training network) offers a timely paradigm for multidisciplinary research, ideal for improving drug repurposing and discovery strategies of compounds, with Autosomal dominant polycystic kidney disease (ADPKD) as example. ADPKD is one of the most common causes of renal failure. Currently, only the vasopressin V2 receptor antagonist tolvaptan (Jinarc®) is approved as treatment in a number of countries, to slow disease progression in patients. Unfortunately, this drug is accompanied by side effects, including polyuria and liver toxicity, restricting its use to a subset of ADPKD patients. The difficulty in identifying drugs for ADPKD treatment can be partially attributed to the lack of understanding of the functions of the PKD1- and PKD2-proteins, and on how inactivation of these two trans-membrane proteins leads to cyst development. The identification of more and better drugs for ADPKD requires a multidisciplinary and macro-level approach. Therefore, repositioning of drugs that are on the market for other diseases is probably the fastest approach to bring new therapies to the clinic. ADPKD is a good paradigm for the development of new drugs combining various approaches, including repurposing and drug discovery.
