CMT2A: a project to study mitochondrial mechanisms and open new therapeutic avenues

CMT2A is a rare neuromuscular disease caused by mutations in the Mitofusin 2 (MFN2) protein, which is localized in the mitochondria. Affected individuals present with sensory alterations, progressive muscle weakness, and limb atrophy, which in many cases progress to the loss of the ability to walk, making even the simplest daily activities difficult.

To date, available therapeutic options are exclusively supportive, and there are no treatments capable of stopping or slowing the degenerative progression of the disease. Among the most promising strategies, gene therapy, aimed at correcting the genetic defect responsible for the condition, represents an important line of research.

In recent years, our group has focused its efforts on developing this approach. Although the results obtained in cellular models have been encouraging, several critical issues still limit its clinical translation. However, these studies have paved the way for a new research paradigm, which goes beyond the concept of a single “defective” gene and instead focuses on biological processes and protein interactions involving MFN2.

This perspective highlights the importance of not limiting research to the disease-associated gene alone, but also examining the interactions in which it is involved, as understanding these relationships is key to identifying more effective therapeutic strategies.

In this context, we have identified Mitofusin 1 (MFN1), a mitochondrial protein that closely interacts with MFN2, as a new and promising therapeutic target. Based on this evidence, we have designed a novel research project aimed at developing an innovative therapeutic protocol, which involves the delivery of the MFN1 gene to compensate for impaired MFN2 levels in CMT2A models.