Benson S. Chen1,2,5 and Patrick Yu-Wai-Man1,2,3,4 1John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0PY, United Kingdom 2Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge CB2 0QQ, United Kingdom 3Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, United Kingdom 4Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom Correspondence: py237cam.ac.uk

↵5 Present address: Gonville and Caius College, Trinity Street, Cambridge CB2 1TA, United Kingdom.

Leber hereditary optic neuropathy (LHON) is a rare, maternally inherited mitochondrial disorder that presents with severe bilateral sequential vision loss, due to the selective degeneration of retinal ganglion cells (RGCs). Since the mitochondrial genetic basis for LHON was uncovered in 1988, considerable progress has been made in understanding the pathogenetic mechanisms driving RGC loss, which has enabled the development of therapeutic approaches aimed at mitigating the underlying mitochondrial dysfunction. In this review, we explore the genetics of LHON, from bench to bedside, focusing on the pathogenetic mechanisms and how these have informed the development of different gene therapy approaches, in particular the technique of allotopic expression with adeno-associated viral vectors. Finally, we provide an overview of the recent gene therapy clinical trials and consider the unanswered questions, challenges, and future prospects.