Experimental gene therapy in mitochondrial disorders

Mitochondrial disorders are a vast group of heterogeneous genetic conditions characterized by single or multiple defects of the mitochondrial respiratory chain (RC), the main source of spendable energy in the cell. The respiratory chain protein structures are expressed by two distinct genomes, the mitochondrial DNA, mtDNA, and the nuclear DNA, nDNA. The mtDNA is localized in multiple copies in each mitochondrion and encodes 13 protein- and 24 translation-associated genes (22 transfer RNAs, tRNA, and 2 ribosomal RNAs, rRNA), which carries out the translation of the 13 genes into subunits of the RC. The nDNA contains approximately 70 genes encoding the remaining subunits of the RC, as well as a huge number of additional genes (ca. 1500), which provide the protein repertoires necessary to control other pathways regulating or associated with the RC. Regrettably, effective therapy for mitochondrial disorders is not available yet. However, once the responsible gene is identified, gene replacement, targeting a wild-type version of the responsible gene to affected tissues, should constitute the gold standard for mitochondrial diseases due to mutations in nuclear genes. Further hurdles must be addressed to develop strategies to correct mtDNA defects, due to its peculiar and complex biology. Our project is specific for nuclear gene defects and is based on the use of new recombinant AAV vectors carrying the therapeutic gene in affected organs, included the brain, the heart and the muscle. We will use recently developed AAV vectors on suitable mouse models to test their safety and efficacy, with the ultimate goal to translate the most promising preclinical results to patients.