RNA-BASED COMBINATORIAL MULTI TARGET THERAPY FOR THE TREATMENT OF INHERITED NEUROMUSCULAR DISEASES

Neuromuscular diseases are still without an effective and curative therapy. Gene therapy can be a response to the need for new treatments, but it presents limitations due to the use of viruses as vectors, which are associated with issues related to the immune response and the efficiency with which muscle fibers are genetically corrected. In addition, patients are diagnosed with neuromuscular diseases and receive gene therapy treatment when muscle mass and strength loss are already evident or even significant. This project proposes an innovative combined approach in which the correction of the mutated gene is accompanied by the activation of signals that promote muscle growth, energy metabolism, and innervation using RNA molecules. Multi target therapies are already used for the treatment of cancer, autoimmune diseases, and, recently, also diabetes and obesity, but they have never been explored in the field of genetic diseases. This project aims to be a pilot study on its feasibility. We will use the most modern technologies for DNA sequence correction along with RNA therapy in three neuromuscular diseases, such as Duchenne muscular dystrophy, Kennedy disease, and mitochondrial pathology due to mutations in the POLG gene. These approaches will be tested both on various murine models of the disease and on neuromuscular organoids derived from patient cells. The project also includes the development of various advanced technologies that will better understand the mechanisms of disease progression. If the project will be successful, it will pave the way for combined treatment also for other neuromuscular diseases.