A New Strategy for SMARD1: The Potential of HDAC Inhibitors

SMARD1 is a severe and extremely rare autosomal recessive neuromuscular disease caused by mutations in the IGHMBP2 gene, which lead to selective motor neuron degeneration, progressive muscle weakness and atrophy, and, in the most severe cases, death from respiratory failure during the first years of life. To date, no approved therapies exist for this condition.

In recent years, gene therapy has emerged as a promising approach to restore IGHMBP2 expression, and our group has contributed significantly to this progress, publishing results demonstrating meaningful benefits in experimental models of SMARD1. However, despite these encouraging findings, several challenges remain that limit the full clinical translation of this approach.

In this context, we have recently demonstrated for the first time the presence of muscle inflammation and fibrosis in the SMARD1 mouse model, identifying new pathological mechanisms that have not been explored before and that may represent relevant therapeutic targets. Preliminary data suggest that intervening on these processes could complement and enhance the gene therapy strategies currently under development.

Based on this evidence, we have designed a new research project focused on the use of histone deacetylase inhibitors (HDACi), molecules capable of modulating multiple biological processes and already shown to be effective in several muscle and neurodegenerative diseases such as Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD), which, like SMARD1, also involve inflammatory and muscular components. Among HDACi, givinostat, recently approved by the FDA for DMD, has demonstrated significant preclinical and clinical benefits in the treatment of this disease due to its anti-inflammatory and anti-fibrotic effects. Despite its success in related neuromuscular diseases, HDACi treatment has never been evaluated in SMARD1 models, leaving its potential impact on disease mechanisms and clinical progression completely unexplored, particularly from a drug repurposing perspective.