AUTHOR=Newman Nancy J. , Yu-Wai-Man Patrick , Carelli Valerio , Biousse Valerie , Moster Mark L. , Vignal-Clermont Catherine , Sergott Robert C. , Klopstock Thomas , Sadun Alfredo A. , Girmens Jean-François , La Morgia Chiara , DeBusk Adam A. , Jurkute Neringa , Priglinger Claudia , Karanjia Rustum , Josse Constant , Salzmann Julie , Montestruc François , Roux Michel , Taiel Magali , Sahel José-Alain 

TITLE=Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison

JOURNAL=Frontiers in Neurology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.662838

DOI=10.3389/fneur.2021.662838

ISSN=1664-2295

ABSTRACT=Objective: 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: Combined analysis of two phase 3 randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluating the efficacy of rAAV2/2-ND4 versus 11 pooled NH studies used as an external control.

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

Methods: 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 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 visual acuity of 208 NH subjects matched for age and ND4 genotype. 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 for statistical inferences.

Main Outcome Measures: 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 BCVA of treated patients progressively improved from Month 12 to Month 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 versus 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: m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies.