Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy.

Abstract

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of -0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.

• Authors: Patrick Yu-Wai-Man, Nancy J Newman, Valerio Carelli, Mark L Moster, Valerie Biousse, Alfredo A Sadun, Thomas Klopstock, Catherine Vignal-Clermont, Robert C Sergott, Günther Rudolph, Chiara La Morgia, Rustum Karanjia, Magali Taiel, Laure Blouin, Pierre Burguière, Gerard Smits, Caroline Chevalier, Harvey Masonson, Yordak Salermo, Barrett Katz, Serge Picaud, David J Calkins, José-Alain Sahel
• Journal: Science translational medicine (Sci Transl Med) Vol. 12 Issue 573 (12 09 2020) ISSN: 1946-6242 [Electronic] United States
• PMID: 33298565 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• NADH Dehydrogenase

Topics

• Animals
• Dependovirus (genetics)
• Genetic Therapy
• NADH Dehydrogenase (genetics)
• Optic Atrophy, Hereditary, Leber (genetics, therapy)
• Tomography, Optical Coherence
• Visual Acuity
• Visual Fields