Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited disease leading to blindness. A mitochondrial DNA point mutation at the 11778 nucleotide site of the NADH dehydrogenase subunit 4 (ND4) gene is the most common cause. The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. Physical examinations included routine blood and urine. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable. No other outcome measure was significantly changed. None of the nine patients had local or systemic adverse events related to the vector during the 9-month follow-up period. These findings support the feasible use of gene therapy for LHON.

Leber's hereditary optic neuropathy (LHON) is a disease that leads to blindness. Gene therapy has been investigated with some success, and could lead to important advancements in treating LHON. This was a prospective, open-label trial involving 9 LHON patients at Tongji Hospital, Wuhan, China, from August 2011 to December 2015. The purpose of this study was to evaluate the long-term outcomes of gene therapy for LHON. Nine LHON patients voluntarily received an intravitreal injection of rAAV2-ND4. Systemic examinations and visual function tests were performed during the 36-month follow-up period to determine the safety and efficacy of this gene therapy. Based on successful experiments in an animal model of LHON, 1 subject also received an rAAV2-ND4 injection in the second eye 12 months after gene therapy was administered in the first eye. Recovery of visual acuity was defined as the primary outcome of this study. Changes in the visual field, visual evoked potential (VEP), optical coherence tomography findings, liver and kidney function, and antibodies against AAV2 were defined as secondary endpoints. Eight patients (Patients 2–9) received unilateral gene therapy and visual function improvement was observed in both treated eyes (Patients 4, 6, 7, and 8) and untreated eyes (Patients 2, 3, 4, 6 and 8). Visual regression fluctuations, defined as changes in visual acuity greater than or equal to 0.3 logMAR, were observed in Patients 2 and 9. Age at disease onset, disease duration, and the amount of remaining optic nerve fibers did not have a significant effect on the visual function improvement. The visual field and pattern reversal VEP also improved. The patient (Patient 1) who received gene therapy in both eyes had improved visual acuity in the injected eye after the first treatment. Unfortunately, visual acuity in this eye decreased 3 months after he received gene therapy in the second eye. Animal experiments suggested that ND4 expression remains stable in the contralateral eye after intravitreal injections. No serious safety problem was observed in the 3-year follow-up of the 9 participants enrolled in this virus-based gene therapy. Meanwhile, our results support the use of intravitreal rAAV2-ND4 as an aggressive maneuver in our clinical trial. Further study in additional patients and in these 9 subjects is needed to better understand the effects of rAAV2-ND4 gene therapy on LHON and to increase the applications of this technique.

Gene therapy may be a promising approach for the treatment of Leber hereditary optic neuropathy. The aim of this study was to evaluate patients with this condition who were recruited into an upcoming gene therapy clinical trial and to assess any changes in the detection parameters to provide support for the clinical trial. Sixteen patients with Leber hereditary optic neuropathy were evaluated using visual function tests 12 months before the initiation of gene therapy. Then, the results of visual acuity (VA), visual field (VF), RNFL (retinal nerve fiber layer) thickness, and Pattern-reversal Visual evoked potential (PR-VEP) were compared and analyzed. A total of 32 eyes of 16 patients were evaluated. Based on the best-corrected visual acuity (BCVA), 24 eyes were relatively stable compared with the baseline evaluation, and 8 eyes had significant changes, including 5 eyes that showed improvement and 3 eyes that showed impairment. In all eyes, the changes in the best-corrected visual acuity were significantly correlated with the changes in the visual field index (VFI), mean defect (MD), and P100 of the visual evoked potential. In the eyes with relatively stable BCVA and those with an obvious improvement in the BCVA, only the visual mean defect showed a significant change; the other indicators were not significantly different. Aside from the patients showing a tendency of spontaneous improvement, the others were in accordance with the requirement. The effects of Leber hereditary optical neuropathy (LHON) gene therapy should be evaluated primarily based on visual acuity. Additionally, visual field, neural fiber thickness, and electrophysiology should be considered in the evaluation.