Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset.
Newman Nancy J, Yu-Wai-Man Patrick, Carelli Valerio, Moster Mark L, Biousse Valerie, Vignal-Clermont Catherine, Sergott Robert C, Klopstock Thomas, Sadun Alfredo A, Barboni Piero
AI Summary
This gene therapy study for early LHON found no significant visual acuity difference between treated and sham eyes, suggesting limited direct benefit from the injection itself.
Abstract
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 × 10 10 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.
MeSH Terms
Shields Classification
Key Concepts5
In a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial (RESCUE) of 38 subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset, the difference of the change in best-corrected visual acuity (BCVA) from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89) at week 48.
The primary end point of a -0.3 logMAR (15-letter) difference in best-corrected visual acuity (BCVA) was not met in a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial (RESCUE) evaluating rAAV2/2-ND4 in 38 subjects with Leber hereditary optic neuropathy.
At 96 weeks after unilateral injection of rAAV2/2-ND4, Leber hereditary optic neuropathy (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 in a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial (RESCUE).
In a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial (RESCUE) of 38 subjects with Leber hereditary optic neuropathy, the mean best-corrected visual acuity (BCVA) for both rAAV2/2-ND4-treated and sham-treated groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48.
In a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial (RESCUE) of 38 subjects with Leber hereditary optic neuropathy, after week 48, an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level was observed in the rAAV2/2-ND4-treated and sham-treated eyes, respectively.
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