Emerging therapies for mitochondrial disorders

Helen Nightingale, Gerald Pfeffer, David Bargiela, Rita Horvath, Patrick F. Chinnery
2016 Brain  
Mitochondrial disorders are a diverse group of debilitating conditions resulting from nuclear and mitochondrial DNA mutations that affect multiple organs, often including the central and peripheral nervous system. Despite major advances in our understanding of the molecular mechanisms, effective treatments have not been forthcoming. For over five decades patients have been treated with different vitamins, co-factors and nutritional supplements, but with no proven benefit. There is therefore a
more » ... ear need for a new approach. Several new strategies have been proposed acting at the molecular or cellular level. Whilst many show promise in vitro, the clinical potential of some is questionable. Here we critically appraise the most promising preclinical developments, placing the greatest emphasis on diseases caused by mitochondrial DNA mutations. With new animal and cellular models, longitudinal deep phenotyping in large patient cohorts, and growing interest from the pharmaceutical industry, the field is poised to make a breakthrough. Abbreviations: AAV = adeno-associated viral vector; Cas9 = clustered regularly interspaced short palindromic repeats associated protein 9; COX = cytochrome c oxidase; LHON = Leber hereditary optic neuropathy; MNGIE = mitochondrial neurogastrointestinal encephalopathy; PARP = poly ADP (adenosine diphosphate-ribose) polymerase; PGC-1 = peroxisome proliferator-activated receptor gamma coactivator-1-alpha; PPARs = peroxisome proliferator-activated receptors; TALENs = transcription activator-like effectors nucleases; ZFN = zinc finger nuclease
doi:10.1093/brain/aww081 pmid:27190030 pmcid:PMC4892756 fatcat:h63gnd7xu5b7rot4iffeep5gke