Nancy J. Newman, Emory University School of Medicine
Patrick Yu-Wai-Man, University of Cambridge; Cambridge University Hospitals; Moorfields Eye Hospital National Health Service Foundation Trust; University College London
Valerio Carelli, Unitá Operativa Compless Clinica Neurologica; University of Bologna
Valerie Biousse, Emory University School of Medicine
Mark Moster, Thomas Jefferson UniversityFollow
Catherine Vignal-Clermont, A. de Rothschild Foundation Hospital; Centre Hospitalier National d'Ophtalmologie des Quinze Vingts
Robert C. Sergott, Thomas Jefferson UniversityFollow
Thomas Klopstock, Ludwig-Maximilians-University Munich; German Center for Neurodegenerative Diseases; Munich Cluster for Systems Neurology
Alfredo A. Sadun, University of California, Los Angeles
Jean-François Girmens, Centre Hospitalier National d'Ophtalmologie des Quinze Vingts
Chiara La Morgia, Unitá Operativa Compless Clinica Neurologica
Adam A. DeBusk, Thomas Jefferson UniversityFollow
Neringa Jurkute, Moorfields Eye Hospital National Health Service Foundation Trust; University College London
Claudia Priglinger, Ludwig-Maximilians-University Munich
Rustum Karanjia, University of California, Los Angeles; University of Ottawa Eye
Constant Josse, eXYSTAT
Julie Salzmann, Medical and Regulatory Consulting
François Montestruc, eXYSTAT
Michel Roux, GenSight Biologics
Magali Taiel, GenSight Biologics
José-Alain Sahel, Sorbonne Université; A. de Rothschild Foundation Hospital; The University of Pittsburgh; Institut Hospitalo-Universitaire FOReSIGHT

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This article is the authors’ final published version in Frontiers in Neurology, Volume 12, May 2021, Article number 662838.

The published version is available at Copyright © Newman et al.


Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies.

Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control.

Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss.

Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences.

Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4.

Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (−0.32 LogMAR, p < 0.0001).

Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies.

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