Full project title:
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)

Aim: The study aimed 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.

Final project summary:
Leprosy is a treatable infectious disease, but more than 200,000 new cases are still reported worldwide each year. During the course of the disease, many patients experience sudden episodes of severe inflammation known as leprosy reactions (LR). These reactions can cause nerve damage and, if not treated promptly, may result in permanent disability.

The standard treatment for leprosy reactions relies mainly on long-term use of corticosteroids or thalidomide. While these medicines can be effective, they are often associated with significant side effects. Identifying safer and more effective treatment options is therefore a major priority.

To support the development of new therapies, this study investigated the genetic factors that increase the risk of leprosy reactions. Understanding the biological mechanisms behind these reactions can help identify new drug targets and reveal opportunities to repurpose existing medicines.

The research focused on the two main types of leprosy reactions: Type 1 Reactions (T1R) and Type 2 Reactions (T2R), also known as Erythema Nodosum Leprosum (ENL).

By studying a large cohort of people affected by leprosy in Vietnam, researchers identified rare genetic variants in four genes associated with an increased risk of Type 1 Reactions. Interestingly, these genes have previously been linked to neurodegenerative diseases such as Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS). This finding suggests that some of the biological pathways involved in these neurological disorders may also play a role in leprosy reactions. As a result, medicines currently used or being tested for Parkinson’s disease and ALS may offer promising opportunities for repurposing as treatments for Type 1 Reactions.

The genetic causes of Type 2 Reactions are less well understood. To address this gap, researchers conducted a genome-wide analysis of a unique group of patients: children and adolescents under 16 years of age who developed severe multibacillary leprosy and Type 2 Reactions. Because these cases occurred at a young age, they were expected to have a strong genetic component.

This analysis identified two genes, FRMD4B and NFASC, that were associated with an increased risk of Type 2 Reactions. The findings were subsequently confirmed in independent patient populations from both Vietnam and Brazil, providing the first strong evidence that these genetic risk factors are shared across different ethnic groups.

Both genes are involved in important biological processes, including nerve function, myelin maintenance, immune responses, and the body's handling of glucocorticoids—the main drugs currently used to treat leprosy reactions. These findings offer new insights into how Type 2 Reactions develop and may help guide the discovery of more targeted therapies in the future.

Overall, this study provides important new knowledge about the genetic mechanisms underlying leprosy reactions and represents the first multi-ethnic genetic investigation of risk factors for Type 2 Reactions. By identifying genes and biological pathways involved in both major forms of leprosy reactions, the research has opened new avenues for treatment development.

Importantly, the findings highlight several compounds already used or under clinical evaluation for Parkinson’s disease as potential candidates for repurposing in the treatment of Type 1 Reactions. Future clinical trials will be needed to determine whether these drugs can safely and effectively reduce inflammation, prevent nerve damage, and offer a safer alternative to current therapies.

Impact

Fava, V. M., Perico, J., Orlova, M., Dallmann-Sauer, M., Xu, Y. Z., Thuc, N. V., ... & Schurr, E. (2025). Bridging pleiotropic mechanisms in leprosy type-1 reactions and neurodegenerative diseases. Scientific Reports.