EMPOWERING MUSCULAR DYSTROPHY TREATMENT: EXPLORING THE POTENTIAL OF IDENTIFIED COMPOUND TO TARGET NUCLEAR FACTOR 1 X

Muscular Dystrophies (MDs) are a group of diseases that cause muscles to weaken and waste away. They also affect breathing and heart function, which can lead to early death in most severe cases. Currently, there is no cure for MDs, and treatments mainly slow the disease's progression. In 2017, we discovered that mice with MD that lack a protein called Nfix showed improvements: these mice had fewer damaged muscle fibers, less inflammation, reduced fibrosis, and better physical abilities. In 2022, we also found that removing Nfix from dystrophic macrophages could ameliorate muscle damage and scarring. Therefore, we screened a library of fluorinated compounds using a technique called 19F-NMR spectroscopy to find potential Nfix inhibitors. We identified a promising compound, ARN2011 (hereafter referred to as FC4) and confirmed that it effectively inhibits Nfix in wild-type and dystrophic mice, as well as in human myoblasts and macrophages in vitro. This project seeks to validate FC4 as a therapeutic agent for MDs by investigating its mechanism of action, optimizing its administration and efficacy in preclinical models, and evaluating its potential in human neuromuscular organoids. Success could pave the way for a groundbreaking therapy that complements existing treatments, significantly improving quality of life for MD patients.