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Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset

Authors :
Irena Tsui
Claudia B. Catarino
Piero Barboni
Günther Rudolph
Nancy J. Newman
Sara Silvestri
Alfredo A. Sadun
Michael Dattilo
Neringa Jurkute
Jean-François Girmens
Cosima Schertler
Magali Taiel
Rustum Karanjia
Claudia Priglinger
Maria K Gemenetzi
Armin Wolf
Manuela Contin
Jasmina Al-Tamami
Thomas Klopstock
James Acheson
Robert C. Sergott
Deborah Gibbs
Rabih Hage
Stephan R. Thurau
Adam A. DeBusk
Lidia Di Vito
Mark L. Moster
Valérie Biousse
Med Lindreth DuBois
Valerio Carelli
Gad Heilweil
Chiara La Morgia
Michele Carbonelli
Andrew Hendrick
Patrick Yu-Wai-Man
Jason H. Peragallo
Gerard Smits
Angelika Pressler
Martin Hildebrandt
Alcides Fernandes Filho
Michael Neuenhahn
Bettina von Livonius
Barrett Katz
Daniel R Muth
Siegfried G. Priglinger
Lauren Leitch-Devlin
Susan Mohamed
William R. Tucker
Maria Massini
Maria Eleftheriadou
Laure Blouin
Catherine Vignal-Clermont
Eman Hawy
Simona Degli Esposti
Heather Tollis
G. Baker Hubbard
Jannah Rutter Dobbs
José-Alain Sahel
Catherine Vignal
Melissa SantaMaria
Julie A. Haller
Emory University School of Medicine
Emory University [Atlanta, GA]
Addenbrooke's Hospital
Cambridge University NHS Trust
Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS)
University of Bologna
Jefferson (Philadelphia University + Thomas Jefferson University)
Fondation Ophtalmologique Adolphe de Rothschild [Paris]
Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)
Ludwig-Maximilians-Universität München (LMU)
University of California [Los Angeles] (UCLA)
University of California
Ludwig Maximilian University [Munich] (LMU)
Institut de la Vision
Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
University of Pittsburgh School of Medicine
Pennsylvania Commonwealth System of Higher Education (PCSHE)
Institut Hospitalo-Universitaire FOReSIGHT
Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-Sorbonne Université (SU)
Newman, NJ
Yu-Wai-Man, P
Carelli, V
Moster, ML
Biousse, V
Vignal-Clermont, C
Sergott, RC
Klopstock, T
Sadun, AA
Barboni, P
DeBusk, AA
Girmens, JF
Rudolph, G
Karanjia, R
Taiel, M
Blouin, L
Smits, G
Katz, B
Sahel, J-A
Vignal, C
Hage, R
Catarino, CB
Priglinger, C
Priglinger, S
Thurau, S
von Livonius, B
Muth, D
Wolf, A
Al-Tamami, J
Pressler, A
Schertler, C
Hildebrandt, M
Neuenhahn, M
Heilweil, G
Tsui, I
Hubbard, GB
Hendrick, A
Dattilo, M
Peragallo, J
Hawy, E
DuBois, Med L
Gibbs, D
Filho, AF
Dobbs, J
Carbonelli, M
Di Vito, L
Contin, M
Mohamed, S
La Morgia, C
Silvestri, S
Acheson, J
Eleftheriadou, M
Esposti, S
Gemenetzi, M
Leitch-Devlin, L
Tucker, WR
Jurkute, N
SantaMaria, M
Tollis, H
Haller, JA
Massini, M.
Source :
Ophthalmology: Journal of The American Academy of Ophthalmology, Ophthalmology: Journal of The American Academy of Ophthalmology, Elsevier, 2021, 128 (5), pp.649-660. ⟨10.1016/j.ophtha.2020.12.012⟩, Ophthalmology 128(5), 649-660 (2021). doi:10.1016/j.ophtha.2020.12.012
Publication Year :
2021
Publisher :
HAL CCSD, 2021.

Abstract

International audience; 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 × 1010 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.

Subjects

Subjects :
Male
Time Factors
Visual acuity
genetic structures
physiology [Visual Fields]
[SDV]Life Sciences [q-bio]
efficacy
Visual Acuity
Phases of clinical research
genetics [Dependovirus]
chemistry.chemical_compound
0302 clinical medicine
Visual Field Test
Quality of life
Clinical endpoint
Contrast (vision)
intravitreal gene therapy
media_common
0303 health sciences
physiology [Visual Acuity]
Diabetic retinopathy
Dependovirus
Middle Aged
Dependoviru
genetics [DNA, Mitochondrial]
Phase 3 randomized double-masked clinical trial
Treatment Outcome
Intravitreal Injections
diagnosis [Optic Atrophy, Hereditary, Leber]
Female
Genetic Vector
medicine.symptom
Human
Adult
safety
LEBER HEREDITARY OPTIC NEUROPATHY
medicine.medical_specialty
retinal anatomic measures
Time Factor
Adolescent
media_common.quotation_subject
psychology [Optic Atrophy, Hereditary, Leber]
Genetic Vectors
Visual Field
Humphrey visual field perimetry
Optic Atrophy, Hereditary, Leber
therapy [Optic Atrophy, Hereditary, Leber]
DNA, Mitochondrial
bilateral visual improvement
Follow-Up Studie
Leber Hereditary Optic Neuropathy
Young Adult
03 medical and health sciences
Double-Blind Method
Ophthalmology
psychology [Quality of Life]
Electroretinography
medicine
Humans
ddc:610
Aged
030304 developmental biology
contrast sensitivity
business.industry
Intravitreal Injection
Retinal
Genetic Therapy
retinal anatomic measure
medicine.disease
eye diseases
genetics [Optic Atrophy, Hereditary, Leber]
chemistry
Mutation
030221 ophthalmology & optometry
Visual Field Tests
sense organs
Visual Fields
business
Follow-Up Studies
best-corrected visual acuity

Details

Language :
English
ISSN :
01616420
Database :
OpenAIRE
Journal :
Ophthalmology: Journal of The American Academy of Ophthalmology, Ophthalmology: Journal of The American Academy of Ophthalmology, Elsevier, 2021, 128 (5), pp.649-660. ⟨10.1016/j.ophtha.2020.12.012⟩, Ophthalmology 128(5), 649-660 (2021). doi:10.1016/j.ophtha.2020.12.012
Accession number :
edsair.doi.dedup.....61639fdbd5cf15223e6676350bc8de96
Full Text :
https://doi.org/10.1016/j.ophtha.2020.12.012⟩