Gene Therapy Leads to Unexpected Bilateral Improvements

Optometrist giving eye exam to senior patient
Researchers compared the treatment effect of rAAV2/2-ND4 with an external control group of untreated patients.

This article is part of Ophthalmology Advisor’s conference coverage from the 2021 meeting of The Association for Research in Vision and Ophthalmology (ARVO), held virtually from May 1 to 7, 2021. The team at Ophthalmology Advisor will be reporting on a variety of the research presented by the eye and vision experts at ARVO. Check back for more from the ARVO 2021 Meeting.


Unilateral rAAV2/2-ND4 gene therapy resulted in unexpected, bilateral improvement in patients with Leber hereditary optic nerve neuropathy, according to research results presented at the Association for Research in Vision and Ophthalmology (ARVO) 2021 Annual Meeting, held May 1 to May 7, 2021. 

Recent results from two phase 3 multicenter clinical trials — RESCUE ( identifier NCT02652767) and REVERSE ( identifier NCT02652780) — demonstrated unexpected, sustained bilateral improvement in best corrected visual acuity (BCVA) after unilateral rAAV2/2-ND4 gene therapy in patients with Leber hereditary optic neuropathy. To evaluate these results, researchers compared the treatment effect of this gene therapy with control patients. 

The study cohort included 76 patients who underwent gene therapy; 62 of these patients enrolled in a long-term follow-up study ( identifier NCT03406104). The control group included 208 participants: 23 enrolled in the REALITY LHON registry ( identifier NCT03295071) and 185 with available individual patient-level data from 10 natural history studies. 

Investigators compared BCVA between treated and untreated patients at 12-, 18-, 24-, 36-, and 48-months following vision loss onset. 

In the cohort of treated patients, BCVA demonstrated “gradual, progressive, and sustained improvement between month 12 and the final available observation (average, 51.5 months). No recovery was noted in the untreated group. At 48 months, mean BCVA was 1.26 logMAR and 1.59 logMAR for treated vs untreated patients, respectively, a difference of 0.33 logMAR or 16.5 ETDRS letters equivalent. 

“This indirect comparison of 76 treated patients with an external control group of 208 untreated patients showed a clinically meaningful effect of gene therapy on visual outcomes in ND4-LHON patients,” the research shows.

Disclosure: Several study authors declared affiliations with the biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

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Yu-Wai-Man P, Newman J, La Morgia CC, et al. Evaluation of the efficacy of rAAV2/2-ND4 gene therapy for Leber hereditary optic neuropathy compared with the natural history. Presented at: Association for Research in Vision and Ophthalmology (ARVO) 2021 Annual Meeting; May 1-7, 2021. Abstract 3498684.