Repurposing drugs to treat cardiovascular disease in the era of precision medicine

Abstract

Drug repurposing is the use of a given therapeutic agent for indications other than that for which it was originally designed or intended. The concept is appealing because of potentially lower development costs and shorter timelines than are needed to produce a new drug. To date, drug repurposing for cardiovascular indications has been opportunistic and driven by knowledge of disease mechanisms or serendipitous observation rather than by systematic endeavours to match an existing drug to a new indication. Innovations in two areas of personalized medicine - computational approaches to associate drug effects with disease signatures and predictive model systems to screen drugs for disease-modifying activities - support efforts that together create an efficient pipeline to systematically repurpose drugs to treat cardiovascular disease. Furthermore, new experimental strategies that guide the medicinal chemistry re-engineering of drugs could improve repurposing efforts by tailoring a medicine to its new indication. In this Review, we summarize the historical approach to repurposing and discuss the technological advances that have created a new landscape of opportunities.

Fig. 1. Drug repositioning by transcriptomic profiling.

Publicly available datasets, such as the NIH LINCS transcriptomic library, facilitate the matching of gene variant effects with drug effects. In the example depicted, defining the transcriptomes of cells treated with short hairpin RNAs to knockdown the activity of a gene of interest generates a putative signature. Cross-referencing against the transcriptional signatures of drug treatments catalogued in the database allows the identification of drugs that might reverse the gene-knockdown signature. When restricted to FDA-approved drugs, this in silico screening leads to drug repurposing candidates that can be validated via in vitro and/or in vivo models. Depending on the current indications and use of the drug in humans, the pathway to a clinical trial and clinical use might be streamlined compared with that for a completely new drug. Another avenue is to perform additional medicinal chemistry work to further optimize the activity of the drug and/or to develop novel compounds. KS, Kolmogorov–Smirnov.

Fig. 2. iPSCs in drug repurposing.

a | Induced pluripotent stem cells (iPSCs), derived from healthy donors or donors carrying genetic variants that predispose them to cardiovascular disease, are directed to differentiate into cardiovascular cell types with the use of protocols that mimic mechanisms of early development. Depending on the presence of gene variants and/or the culture conditions, the differentiated derivative cells can display phenotypes that are consistent with a genetic or acquired disease. b | These iPSC models are used to screen drug repurposing candidates, resulting in the identification of drugs for preclinical and clinical testing. c | If the drug candidates have remediable limitations for their new indication, they can be refined through iterative cycles of medicinal chemical optimization and in vitro testing, aided by iPSC-based assays.