Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset

Ophthalmology. 2021 May;128(5):649-660. doi: 10.1016/j.ophtha.2020.12.012. Epub 2021 Jan 12.


Purpose: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).

Design: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial.

Participants: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included.

Methods: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye.

Main outcome measures: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96.

Results: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively.

Conclusions: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.

Trial registration: ClinicalTrials.gov NCT02652767.

Keywords: Humphrey visual field perimetry; Leber Hereditary Optic Neuropathy; Phase 3 randomized double-masked clinical trial; Quality of life; best-corrected visual acuity; bilateral visual improvement; contrast sensitivity; efficacy; intravitreal gene therapy; retinal anatomic measures; safety.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • DNA, Mitochondrial / genetics
  • Dependovirus / genetics
  • Double-Blind Method
  • Electroretinography
  • Female
  • Follow-Up Studies
  • Genetic Therapy*
  • Genetic Vectors
  • Humans
  • Intravitreal Injections
  • Male
  • Middle Aged
  • Mutation
  • Optic Atrophy, Hereditary, Leber / diagnosis
  • Optic Atrophy, Hereditary, Leber / genetics
  • Optic Atrophy, Hereditary, Leber / psychology
  • Optic Atrophy, Hereditary, Leber / therapy*
  • Quality of Life / psychology
  • Time Factors
  • Treatment Outcome
  • Visual Acuity / physiology
  • Visual Field Tests
  • Visual Fields / physiology
  • Young Adult


  • DNA, Mitochondrial

Associated data

  • ClinicalTrials.gov/NCT02652767