Journal Article

The rAAV2-ND1 gene therapy for Leber hereditary optic neuropathy

Dan, Yanping, Li, Bin, Yuan, Jun, Qi, Jia, Ruan, Kunwei, Li, Xin, Zhang, Yong

2025

Overview

Purpose No effective treatment for leber hereditary optic neuropathy (LHON) caused by ND1 mutation is available.This study evaluated the safety and efficacy of a single unilateral intravitreal injection rAAV2- ND1 in various doses for the treatment of LHON. Methods Twelve patients with LHON ( ND1 mutation) in two groups with six participants each.The low-dose group received injection of rAAV2- ND1 in a dose of 1.5 × 10 8 vg/eye while the high-dose group received 1.5 × 10 9 vg/eye.The safety endpoint was the incidence of adverse events (AEs).The primary efficacy endpoint was changes of best corrected visual acuity (BCVA).The secondary efficacy endpoints were improvement in visual field (VF), visual field index (VFI), and mean deviation (MD) and change in retinal nerve fiber layer (RNFL) thickness. Results In total,11 mild eye-related AEs occurred in the participants in both groups, and short-term drug treatment returned to normal.The difference was statistically significant in BCVA of the injected eyes in the low-dose group between 12 months after treatment and at baseline.The differences in BCVA of the uninjected eyes in the high-dose group between baseline and 3 months or 6 months after treatment were statistically significant.At 12 months after treatment, the rate of improvement in BCVA for the injected eyes in the low-dose groups was 66.7% (4/6),while BCVA for the uninjected eyes in the high-dose groups was 50.0% (3/6),and patients in both groups had binocular VF (VFI, MD) and RNFL thicknesses that did not significantly differ from baseline. Conclusion Preliminary clinical evidence shows that rAAV2- ND1 ophthalmic injection is a safe and effective treatment for LHON due to ND1 mutation. Trial Registration Trial registration number: ChiCTR2000041574, Date:12/29/2020. Key messages What is known Currently, the focus on Leber hereditary optic neuropathy (LHON) caused by the most common ND4 gene mutation, whereas little is done on LHON caused by the less common ND1 mutation. What is new Gene therapy LHON ((ND1 mutation)) is safe and effective. Monocular gene therapy, LHON patients can improve binocular vision function. Gene therapy needs to further explore the optimal therapeutic titer, not the higher the titer, the better the therapeutic effect.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V
• Subject: Acuity / Adolescent / Adult / Binocular vision / Clinical trials / Dependovirus - genetics / Disease / Drug dosages / Eye / Female / Follow-Up Studies / Gene therapy / Genetic Therapy - methods / Genetic Vectors - administration & dosage / Humans / Immunity (Disease) / Informed consent / Injection / Intravitreal Injections / Male / Medicine / Medicine & Public Health / Middle Aged / Mitochondrial DNA / Mutation / NADH Dehydrogenase - genetics / ND1 gene / ND4 gene / Nerve Fibers - pathology / Neurophthalmology / Ophthalmology / Optic Atrophy, Hereditary, Leber - diagnosis / Optic Atrophy, Hereditary, Leber - genetics / Optic Atrophy, Hereditary, Leber - physiopathology / Optic Atrophy, Hereditary, Leber - therapy / Optic neuropathy / Patients / Point mutation / Proteins / Registration / Retinal Ganglion Cells - pathology / Statistical analysis / Surgery / Tomography, Optical Coherence - methods / Treatment Outcome / Visual Acuity / Visual field / Visual Fields - physiology / Young Adult