Knockdown and Replacement of MFN2: a Gene Therapy to treat Dominantly Inherited Peripheral Neuropathy CMT2A

Charcot-Marie-Tooth Disease 2A (CMT2A) is a severe and disabling sensory-motor axonopathy characterized by the death of motor and sensory neurons. The pathology is caused by mutations in the Mitofusin 2 (MFN2) gene, that codes for the MFN2 protein, located in the membrane of the mitochondria, a cellular organelle, which represents the power station of cells. As yet, unfortunately, no resolute therapy is available. Gene therapy represents a promising strategy as it is aimed at correcting the genetic cause underlying the disease itself. In the case of this disease, not only the lack of the "healthy" gene, but also the presence of the "sick" MFN2 protein are the cause of the pathology. The objective of this study is therefore to develop a therapeutic approach for this pathology based on the silencing of the pathological MFN2 gene in combination with the administration of the normal MFN2 gene, using a single adeno-associated vector of type 9 (AAV9) modified to perform both functions. This therapeutic strategy will be properly validated in animal models of the disease. Since the currently available animal models do not fully reproduce disease phenotype, part of the project will be also focused on the generation of new CMT2A animal models, through the expression of genetic defects identified more frequently in patients. The availability of more reliable disease models is essential to verify the effectiveness of therapeutic strategies. In conclusion, our approach could represent the first effective treatment for CMT2A and have a broad translational impact on other genetic component neuromuscular disorders.