A recent study conducted by researchers from the “Dino Ferrari Center”, University of Milan, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico, and accepted for online publication in the rivista Cellular Molecular Life Science, has demonstrated the effectiveness of a gene therapy approach in an experimental model of Charcot-Marie-Tooth disease type 2A (CMT2A).

CMT2A is a sensorimotor polyneuropathy associated with mutations in the Mitofusin 2 (MFN2) gene and characterized by the degeneration of motor and sensory axons in the peripheral nerves. Currently, the treatment is supportive and there is no effective therapy in preventing the disease-related neurodegeneration. One of the main challenges in the treatment of this pathology lies not only in the absence of the functional MFN2 protein, but also in the presence of a toxic variant of this protein. A combined approach of gene replacement and silencing, respectively capable of expressing the “healthy” gene and switching off the “sick” one, may constitute an ideal therapeutic approach for this disease.

The principal investigator of this research is Prof. Stefania Corti, currently head of the Neural Stem Cell Laboratory in the Department of Pathophysiology and Transplantation of the University of Milan. The research group included other members of the laboratory and researchers from the “Dino Ferrari Center” of the University of Milan and from the IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico. In addition, the group collaborated with King’s College, the “Romeo ed Enrica Invernizzi” Institute of Molecular Genetics, the Department of Biomedical Sciences of the Humanitas University, the Carlo Besta Neurological Institute and the Preclinical research center of the IRCCS Ca’ Granda Ospedale Maggiore Policlinico Foundation.

Dr. Federica Rizzo, first author of this research work, and her colleagues demonstrated how this combined approach of silencing the defective MFN2 gene and restoring the healthy gene led to an improvement in the characteristics of the disease in an in vitro model consisting of motor neurons derived from induced pluripotent stem cells of patients affected by CMT2A.

The molecular correction was also confirmed in a mouse model of CMT2A by local injection into the Central Nervous System of an Adeno-Associated AAV9 vector carrying the healthy MFN2 gene and the silencing construct.

This study provides the first “proof of principle” of the effectiveness of this treatment for CMT2A and testifies the perseverance of Prof Corti’s research group in studying this pathology and identifying possible therapeutic strategies.

The research was conducted with the support of the Associazione Dino Ferrari Center, dell’Associazione Progetto Mitofusina2 onlus, of the Ministry of Health, as part of the Young Researchers Research Project – GR- 2018-12365358 funded 2018–2021, and of the Telethon Foundation as part of the GGP19002 project.

Combined RNA interference and gene replacement therapy targeting MFN2 as proof of principle for the treatment of Charcot-Marie-Tooth type 2A

Federica Rizzo ¹, Silvia Bono ¹, Marc David Ruepp ², Sabrina Salani ¹, Linda Ottoboni ¹, Elena Abati ¹, Valentina Melzi ¹, Chiara Cordiglieri ³, Serena Pagliarani ¹, Roberta De Gioia ¹, Alessia Anastasia ¹, Michela Taiana ¹, Manuela Garbellini ¹, Simona Lodato ^4 5, Paolo Kunderfranco ^4 5, Daniele Cazzato ⁶, Daniele Cartelli ⁶, Caterina Lonati ⁷, Nereo Bresolin ^1 8, Giacomo Comi ^1 8, Monica Nizzardo ^# 1, Stefania Corti ^# 9 10