To investigate the association between the rehabilitation of visual function and retinal nerve fiber layer (RNFL) thickness in Leber hereditary optic neuropathy (LHON) patients receiving gene therapy for the disease.

A multi-center, non-randomized, single-arm clinical trial was conducted.A total of 159 LHON patients were enrolled in Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Taihe Hospital and Ezhou Central Hospital from December 2017 to December 2018.All of the patients were administered with a single unilateral intravitreal injection (0.05 μl) of recombinant adeno-associated virus 2 carrying reduced nicotinamide adenine dinucleotide dehydrogenase subunit 4 (rAAV2-ND4) and were followed up before and 1, 3, 6 and 12 months after treatment.The best corrected visual acuity (BCVA) converted to logarithm of the minimum angle of resolution (LogMAR) unit was assessed with a standard logarithmic visual acuity chart.Perimetry indicators including visual field index (VFI) and mean deviation (MD) were measured with Humphrey Field Analyzer.RNFL thickness in the superior, inferior, temporal, nasal optic disc and the average RNFL thickness were detected with Spectralis^® HRA+ OCT.The 12-month postoperative BCVA, visual field, and RNFL thickness were taken as the primary outcomes.According to the improvement of BCVA, VFI and MD at 12 months after therapy, there were 81 vision improved eyes with injection, 62 vision unimproved eyes with injection, 65 vision improved eyes without injection, and 78 vision unimproved eyes without injection, 48 VFI improved eyes with injection, 71 VFI unimproved eyes with injection, 47 VFI improved eyes without injection, and 72 VFI unimproved eyes without injection, 52 MD improved eyes with injection, 67 MD unimproved eyes with injection, 47 MD improved eyes without injection, and 72 MD unimproved eyes without injection.The correlations between BCVA, VFI, MD and RNFL thickness were evaluated by Pearson linear correlation analysis.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committees of Wuhan Tongji Hospital (No.TJ-IRB20180316), Taihe Hospital (No.2017-01), Ezhou Central Hospital (No.2017-K-05) and People's Hospital of Wuhan University (No.WDRY2020-K202).Written informed consent was obtained from each patient or custodian prior to entering the study cohort.

Among the patients receiving rAAV-ND4 gene therapy, the 12-month postoperative BCVA (LogMAR) in the injected eyes and uninjected eyes was 1.37±0.55 and 1.29±0.59, which were significantly better than 1.70±0.41 and 1.53±0.51 before treatment (baseline), respectively (t=4.920, 3.550; both at P<0.001).The 12-month postoperative VFI of the patients were significantly improved and the 12-month postoperative MD of the patients were significantly lowered in comparison with those at baseline in the injected eyes (both at P<0.001).Similar improvements of VFI and MD were observed in the uninjected eyes (both at P<0.01).RNFL of the patients was thinner after the therapy.In the vision improved eyes with injection, the BCVA was negatively correlated with superior, inferior, temporal, nasal and average RNFL thickness (r=-0.362, -0.292, -0.307, -0.308; all at P<0.05).In the VFI improved eyes with injection, VFI was positively correlated with superior, inferior, nasal and average RNFL thickness (r=0.439, 0.356, 0.294, 0.401; all at P<0.05).In the MD improved eyes with injection, MD was positively correlated with superior, inferior, nasal and average RNFL thickness (r=0.495, 0.424, 0.377, 0.474; all at P<0.05).

The recovery of visual function is associated with RNFL thickness after the intravitreal injection of rAAV2-ND4 in LHON eyes.Recovery of visual acuity is better in the eyes with thicker RNFL.

Gene therapy; Optic atrophy, hereditary, Leber/therapy; Visual acuity; Visual fields; Retinal nerve fiber layer thickness; Human; Tomography, optical coherence; Recombinant adeno-associated virus; NADH dehydrogenase subunit 4