Mitochondrial diseases are clinically, biochemically and genetically heterogeneous disorders of two genomes, for which effective curative
therapies are currently lacking. With the exception of a few rare
vitamin/cofactor responsive conditions (including ACAD9 deficiency, disorders of
coenzyme Q(10) biosynthesis, and
Leigh syndrome caused by mutations in the SLC19A3 transporter), the mainstay of treatment for the vast majority of patients involves supportive measures. The search for a cure for
mitochondrial disease is the subject of intensive research efforts by many investigators across the globe, but the goal remains elusive. The clinical and genetic heterogeneity, multisystemic nature of many of these disorders, unpredictable natural course, relative inaccessibility of the mitochondrion and lack of validated, clinically meaningful outcome measures, have all presented great challenges to the design of rigorous clinical trials. This review discusses barriers to developing effective
therapies for
mitochondrial disease, models for evaluating the efficacy of novel treatments and summarises the most promising emerging
therapies in six key areas: 1)
antioxidant approaches; 2) stimulating mitochondrial biogenesis; 3) targeting mitochondrial membrane
lipids, dynamics and mitophagy; 4) replacement
therapy; 5) cell-based
therapies; and 6) gene therapy approaches for both
mtDNA and nuclear-encoded defects of mitochondrial metabolism.