The study aims at achieving a better understanding of the biological mechanisms involved in leprosy reactions(LR), to safely and effectively repurpose drugs to treat LR and prevent permanent disabilities.

Identifying targets for drug repurposing in leprosy reactions via genetic susceptibility factors

Project coordination

• Research Institute of the McGill University Health Centre (MUHC)
• Instituto Lauro de Souza Lima (ILSL)

Project summary

Leprosy is a treatable infectious disease that every year affects more than 200,000 people worldwide. During the course of leprosy pathogenesis, a considerable proportion of patients experience sudden episodes of host excessive inflammatory responses known as leprosy reactions (LR). The driven causes for LR episodes are not known but they require prompt intervention to prevent permanent disabilities. The therapeutical management of LR episodes are carried out by administering long-term glucocorticoid therapies or thalidomide, which have strong risks of multiple adverse effects. Hence, novel or repurposed drug therapies for LR are essential to improve patient care in leprosy.

To safely and effectively repurpose drugs used to treat other inflammatory conditions to LR, the researchers aim at achieving a better understanding of the biological mechanisms involved in LR. Identifying host genetic risk factors is a means to describe critical mediators of LR and pinpoint drug targetable pathways. There are two major types of LR, Type-1 reaction (T1R) and Erythema Nodosum Leprosum (ENL). T1R is characterized by episodes of acute and sustained inflammation in the periphery. By studying leprosy-affected individuals in the Vietnamese population the research group identified mutations in LRRK2/GAK and PRKN/PINK1 genes shared between T1R and Parkinson’s Disease (PD). The validation of these genes in an independent population from Brazil is essential as drugs targeting specifically LRRK2 or PRKN pathways are undergoing clinical trials and are promising candidates for drug repurposing to manage T1R.

ENL is the second major type of LR. ENL episodes can be chronic with patients usually experience systemic symptoms. Genetic studies of ENL are few and the biological mechanisms involved in the ENL pathogenesis are poorly known. We propose to study families with rare early-onset ENL cases, which are enriched for genetic-risk factors, to identify key genes involved in the disease pathogenesis. These genes will then be candidates to be tested in independent case-control samples from Brazil and Vietnam. This strategy will allow the identification of critical pathways as potential targets for novel treatments in ENL.

Based on the research group’s past research, the present study is expected to have deliverables of direct translatable impact by highlighting existent drugs with reasonable potential for repurposing to treat LR and prevent permanent disabilities.