Efficacy and Safety of Intravitreal rAAV2-ND4 Therapy for Leber’s Hereditary Optic Neuropathy

Background: This study aimed to assess the safety and efficacy of a rAAV2 carrying normal ND4 (rAAV2-ND4) (NR082) in individuals with visual loss due to LHON carrying the m.11778G > A mutation. Additionally, it aimed to determine a safe dose of NR082 for intravitreal injection. Methods: This is a single-arm, open-label, dose-finding clinical trial. A total of 12 participants with the m.11778G > A mitochondrial DNA mutation and vision loss exceeding 6 months in both eyes were enrolled in this trial. The participants received NR082 by unilateral intravitreal injections. 6 participants were received 1.5*10 ⁹ vg, 0.05mL (Group I), and 6 participants received 4.5*10 ⁹ vg, 0.05mL (Group II) and were followed for 52 weeks and underwent ocular and systemic safety assessments, with visual structure and function examinations. Results In Group I, baseline best-corrected visual acuity (BCVA) in injected eyes improved from 1.86 ± 0.36 LogMAR at baseline to 1.59 ± 0.10 LogMAR at week 52 post intravitreal rAAV2-ND4. In Group II, baseline BCVA was 2.15 ± 0.23 LogMAR, improving to 1.92 ± 0.32 LogMAR at week 52. Two eyes in Group I and four eyes in Group II showed significant improvement after 52 week. No serious ocular or systemic adverse events or dose-limiting toxicity were reported. Adverse events possibly related to treatment included uveitis, subconjunctival hemorrhage, vitreous opacity and keratic precipitates. Conclusion This phase 1/2 trial in LHON demonstrated no serious safety concerns in the 12 participants. Further follow-up of these and additional participants is required to confirm these findings.