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1. Incidence and Outcomes of Eye Trauma Associated With Recreative Use of Nonpowder Toy Guns: A 12-Year Retrospective Study.

Author

Dentel A, Boulanger E, Chapron T, Senicourt L, Metge F, Dureau P, Vignal-Clermont C, Caputo G, and Martin GC

Subjects
Humans, Retrospective Studies, Male, Female, Adult, Adolescent, Incidence, Child, Young Adult, Middle Aged, Child, Preschool, Recreation, Aged, Firearms, Wounds, Gunshot epidemiology, Follow-Up Studies, Play and Playthings injuries, Eye Injuries epidemiology, Eye Injuries etiology, Visual Acuity physiology
Abstract

Purpose: Nonpowder toy guns (NPTGs) are responsible for many ocular traumas. This study aims to detail the outcomes of these injuries depending on the causative NPTG., Design: Retrospective, observational case series., Methods: Cases of NPTG-associated ocular trauma managed in a Parisian eye emergency department between August 1, 2010, and January 1, 2023, were reviewed. The date of trauma, causative NPTG, patient demographics, initial and follow-up eye examinations, any surgical procedure, and visual outcomes for each ocular trauma were analyzed., Results: Over 12 years, NPTGs were responsible for 324 eye injuries and 980 visits. Patients were mostly male (77.5%), and mean age at trauma was 16.2 years. Foam bullets or foam dart blasters accounted for 54.9% of traumas and were mainly responsible for corneal injuries and hyphema (30.9% and 27%, respectively). BB guns and airsoft guns were frequently responsible for anterior segment lesions, as well as intravitreal hemorrhages (14.7%) and commotio retinae (21.1%). Paintball guns accounted for the largest proportion of posterior segment lesions (eg, intraretinal or subretinal hemorrhages leading to macular atrophy/contusion maculopathy), and one-third of casualties had undergone ocular surgery. Among all traumas, final visual acuity was lower than 20/200 in 6.5% of cases. Phthisis occurred in 8 cases: Two were related to foam bullets or foam dart blaster injuries (1 contusion and 1 rupture), 2 other cases followed a rupture due to BB guns/airsoft guns, 1 case occurred after a rupture related to a paintball gunshot, and 3 others were due to other types of compressed air guns (1 rupture, 1 intraocular foreign body, and 1 total retinal detachment)., Conclusions: NPTG-related ocular trauma outcomes differ according to the causative toy. Paintball guns and BB guns/airsoft gun-related traumas were more likely to be associated with severe lesions, but an increasing number of ocular injuries related to the use of foam bullets or foam dart blasters are reported in younger and younger children. Public health policies should promote the use of protective eyewear., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Published
2024
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2. Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE Study.

Author

Biousse V, Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Vignal-Clermont C, Klopstock T, Sadun AA, Sergott RC, Hage R, Esposti S, La Morgia C, Priglinger C, Karanja R, Blouin L, Taiel M, and Sahel JA

Subjects
Adolescent, Adult, Aged, DNA, Mitochondrial genetics, Double-Blind Method, Female, Follow-Up Studies, Humans, Intravitreal Injections, Male, Middle Aged, Mutation, NADH Dehydrogenase genetics, NADH Dehydrogenase metabolism, Optic Atrophy, Hereditary, Leber genetics, Optic Atrophy, Hereditary, Leber physiopathology, Quality of Life, Time Factors, Tomography, Optical Coherence, Young Adult, Genetic Therapy methods, Optic Atrophy, Hereditary, Leber therapy, Recombinant Proteins administration & dosage, Visual Acuity, Visual Fields
Abstract

Background: RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials., Methods: In RESCUE and REVERSE, 76 subjects with LHON because of the m.11778 G>A mutation in the mitochondrial gene ND4 received a single unilateral intravitreal injection of lenadogene nolparvovec. After 96 weeks, 61 subjects were enrolled in the long-term follow-up study RESTORE. The best-corrected visual acuity (BCVA) was assessed over a period of up to 52 months after onset of vision loss. A locally estimated scatterplot smoothing regression model was used to analyze changes in BCVA over time. Vision-related quality of life was reported using the visual function questionnaire-25 (VFQ-25)., Results: The population of MT-ND4 subjects enrolled in RESTORE was representative of the combined cohorts of RESCUE and REVERSE for mean age (35.1 years) and gender distribution (79% males). There was a progressive and sustained improvement of BCVA up to 52 months after the onset of vision loss. The final mean BCVA was 1.26 logarithm of the minimal angle of resolution 48 months after the onset of vision loss. The mean VFQ-25 composite score increased by 7 points compared with baseline., Conclusion: The treatment effect of lenadogene nolparvovec on BCVA and vision-related quality of life observed 96 weeks (2 years) after treatment in RESCUE and REVERSE was sustained at 3 years in RESTORE, with a maximum follow-up of 52 months (4.3 years) after the onset of vision loss., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the North American Neuro-Opthalmology Society.)

Published
2021
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3. Cross-Sectional Analysis of Baseline Visual Parameters in Subjects Recruited Into the RESCUE and REVERSE ND4-LHON Gene Therapy Studies.

Author

Moster ML, Sergott RC, Newman NJ, Yu-Wai-Man P, Carelli V, Bryan MS, Smits G, Biousse V, Vignal-Clermont C, Klopstock T, Sadun AA, DeBusk AA, Carbonelli M, Hage R, Priglinger S, Karanjia R, Blouin L, Taiel M, Katz B, and Sahel JA

Subjects
Adolescent, Adult, Aged, Cross-Sectional Studies, DNA, Mitochondrial genetics, Double-Blind Method, Female, Humans, Male, Middle Aged, Optic Atrophy, Hereditary, Leber genetics, Optic Atrophy, Hereditary, Leber therapy, Retinal Ganglion Cells pathology, Tomography, Optical Coherence methods, Young Adult, Genetic Therapy methods, Optic Atrophy, Hereditary, Leber physiopathology, Visual Acuity, Visual Fields physiology
Abstract

Objective: This report presents a cross-sectional analysis of the baseline characteristics of subjects with Leber hereditary optic neuropathy enrolled in the gene therapy trials RESCUE and REVERSE, to illustrate the evolution of visual parameters over the first year after vision loss., Methods: RESCUE and REVERSE were 2 phase III clinical trials designed to assess the efficacy of rAAV2/2-ND4 gene therapy in ND4-LHON subjects. At enrollment, subjects had vision loss for ≤6 months in RESCUE, and between 6 and 12 months in REVERSE. Functional visual parameters (best-corrected visual acuity [BCVA], contrast sensitivity [CS], and Humphrey Visual Field [HVF]) and structural parameters assessed by spectral-domain optical coherence tomography were analyzed in both cohorts before treatment. The cross-sectional analysis of functional and anatomic parameters included the baseline values collected in all eyes at 2 different visits (Screening and Inclusion)., Results: Seventy-six subjects were included in total, 39 in RESCUE and 37 in REVERSE. Mean BCVA was significantly worse in RESCUE subjects compared with REVERSE subjects (1.29 and 1.61 LogMAR respectively, P = 0.0029). Similarly, mean CS and HVF were significantly more impaired in REVERSE vs RESCUE subjects (P < 0.005). The cross-sectional analysis showed that the monthly decrease in BCVA, ganglion cell layer macular volume, and retinal nerve fiber layer thickness was much more pronounced in the first 6 months after onset (+0.24 LogMAR, -0.06 mm3, and -6.00 μm respectively) than between 6 and 12 months after onset (+0.02 LogMAR, -0.01 mm3, and -0.43 μm respectively)., Conclusion: LHON progresses rapidly in the first months following onset during the subacute phase, followed by relative stabilization during the dynamic phase., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the North American Neuro-Opthalmology Society.)

Published
2021
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4. Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene: A Secondary Analysis of a Phase 1/2 Clinical Trial.

Author

Bouquet C, Vignal Clermont C, Galy A, Fitoussi S, Blouin L, Munk MR, Valero S, Meunier S, Katz B, Sahel JA, and Thomasson N

Subjects
Dependovirus, Electroretinography, Female, Fluorescein Angiography methods, Follow-Up Studies, Fundus Oculi, Genetic Vectors administration & dosage, Humans, Intravitreal Injections, Male, Middle Aged, Optic Atrophy, Hereditary, Leber diagnosis, Retrospective Studies, Tomography, Optical Coherence methods, Visual Fields, Genetic Therapy methods, NADH Dehydrogenase genetics, Optic Atrophy, Hereditary, Leber therapy, Parvovirinae genetics, Recombinant Fusion Proteins administration & dosage, Retinal Ganglion Cells pathology, Visual Acuity
Abstract

Importance: Intravitreal gene therapy is regarded as generally safe with limited mild adverse events, but its systemic effects remain to be investigated., Objective: To examine the association between immune response and intraocular inflammation after ocular gene therapy with recombinant adeno-associated virus 2 carrying the ND4 gene (rAAV2/2-ND4)., Design, Setting, and Participants: This secondary analysis of an open-label, dose-escalation phase 1/2 randomized clinical trial of rAAV2/2-ND4 included data from February 13, 2014 (first patient visit), to March 30, 2017 (last patient visit at week 96), the first 2 years after injection. Patients older than 15 years with diagnosed ND4 Leber hereditary optic neuropathy (LHON) and visual acuity of at least counting fingers were enrolled in 1 of 5 cohorts. Four dose cohorts of 3 patients each were treated sequentially. An extension cohort of 3 patients received the dose of 9 × 1010 viral genomes per eye., Interventions: Patients received increasing doses of rAAV2/2-ND4 (9 × 109, 3 × 1010, 9 × 1010, and 1.8 × 1011 viral genomes per eye) as a single unilateral intravitreal injection. Patients were monitored for 96 weeks after injection; ocular examinations were performed regularly, and blood samples were collected for immunologic testing., Main Outcomes and Measures: A composite ocular inflammation score (OIS) was calculated based on grades of anterior chamber cells and flare, vitreous cells, and haze according to the Standardization of Uveitis Nomenclature. The systemic immune response was quantified by enzyme-linked immunospot (cellular immune response), enzyme-linked immunosorbent assay (IgG titers), and luciferase assay (neutralizing antibody [NAb] titers)., Results: The present analysis included 15 patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) enrolled in the 5 cohorts of the clinical trial. Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration. Mild anterior chamber inflammation and vitritis were reported at all doses, and all cases were responsive to treatment. A maximum OIS of 9.5 was observed in a patient with history of idiopathic uveitis. Overall, OIS was not associated with the viral dose administered. No NAbs against AAV2 were detected in aqueous humor before treatment. Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment. Humoral immune response was not apparently associated with the dose administered or with the immune status of patients at baseline. No association was found between OISs and serum NAb titers., Conclusions and Relevance: In this study, intravitreal administration of rAAV2/2-ND4 in patients with LHON was safe and well tolerated. Further investigations may shed light into the local immune response to rAAV2/2-ND4 as a potential explanation for the observed intraocular inflammation.

Published
2019
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5. Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE Study

Author

Biousse, Valérie, Newman, Nancy J, Esposti, Simona, La Morgia, Chiara, Priglinger, Claudia, Karanja, Rustum, Blouin, Laure, Taiel, Magali, Sahel, José-Alain, Group, LHON Study, Yu-Wai-Man, Patrick, Carelli, Valerio, Moster, Mark L, Vignal-Clermont, Catherine, Klopstock, Thomas, Sadun, Alfredo A, Sergott, Robert C, Hage, Rabih, Biousse V., Newman N.J., Yu-Wai-Man P., Carelli V., Moster M.L., Vignal-Clermont C., Klopstock T., Sadun A.A., Sergott R.C., Hage R., Esposti S., La Morgia C., Priglinger C., Karanja R., Blouin L., Taiel M., Sahel J.-A., Emory University School of Medicine, Emory University [Atlanta, GA], University College of London [London] (UCL), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Jefferson (Philadelphia University + Thomas Jefferson University), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Ludwig-Maximilians-Universität München (LMU), University of California [Los Angeles] (UCLA), University of California, National Institute for Health Research Moorfields Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, GenSight Biologics, Institut de la Vision, and Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Visual acuity, Time Factors, genetic structures, Genetic enhancement, Visual Acuity, NADH dehydrogenase subunit 4, 0302 clinical medicine, Quality of life, education.field_of_study, metabolism [NADH Dehydrogenase], physiopathology [Optic Atrophy, Hereditary, Leber], Original Contribution, Recombinant Protein, Middle Aged, genetics [DNA, Mitochondrial], Recombinant Proteins, Intravitreal Injections, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, medicine.symptom, Tomography, Optical Coherence, Human, Adult, medicine.medical_specialty, LEBER HEREDITARY OPTIC NEUROPATHY, Composite score, Time Factor, Adolescent, Long term follow up, Population, Optic Atrophy, Hereditary, Leber, therapy [Optic Atrophy, Hereditary, Leber], DNA, Mitochondrial, Follow-Up Studie, 03 medical and health sciences, Young Adult, methods [Genetic Therapy], Double-Blind Method, Ophthalmology, administration & dosage [Recombinant Proteins], medicine, Humans, ddc:610, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, education, Aged, business.industry, Intravitreal Injection, NADH Dehydrogenase, Genetic Therapy, eye diseases, Clinical trial, genetics [Optic Atrophy, Hereditary, Leber], Mutation, 030221 ophthalmology & optometry, Quality of Life, Neurology (clinical), Visual Fields, genetics [NADH Dehydrogenase], business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Supplemental Digital Content is Available in the Text., Background: RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials. Methods: In RESCUE and REVERSE, 76 subjects with LHON because of the m.11778 G>A mutation in the mitochondrial gene ND4 received a single unilateral intravitreal injection of lenadogene nolparvovec. After 96 weeks, 61 subjects were enrolled in the long-term follow-up study RESTORE. The best-corrected visual acuity (BCVA) was assessed over a period of up to 52 months after onset of vision loss. A locally estimated scatterplot smoothing regression model was used to analyze changes in BCVA over time. Vision-related quality of life was reported using the visual function questionnaire-25 (VFQ-25). Results: The population of MT-ND4 subjects enrolled in RESTORE was representative of the combined cohorts of RESCUE and REVERSE for mean age (35.1 years) and gender distribution (79% males). There was a progressive and sustained improvement of BCVA up to 52 months after the onset of vision loss. The final mean BCVA was 1.26 logarithm of the minimal angle of resolution 48 months after the onset of vision loss. The mean VFQ-25 composite score increased by 7 points compared with baseline. Conclusion: The treatment effect of lenadogene nolparvovec on BCVA and vision-related quality of life observed 96 weeks (2 years) after treatment in RESCUE and REVERSE was sustained at 3 years in RESTORE, with a maximum follow-up of 52 months (4.3 years) after the onset of vision loss.

Published
2020
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6. Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset

Author

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, and Massini, M.

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
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.

Published
2021
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7. 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

Author

Nancy J. Newman, Patrick Yu-Wai-Man, Valerio Carelli, Valerie Biousse, Mark L. Moster, Catherine Vignal-Clermont, Robert C. Sergott, Thomas Klopstock, Alfredo A. Sadun, Jean-François Girmens, Chiara La Morgia, Adam A. DeBusk, Neringa Jurkute, Claudia Priglinger, Rustum Karanjia, Constant Josse, Julie Salzmann, François Montestruc, Michel Roux, Magali Taiel, José-Alain Sahel, Yu Wai Man, Patrick [0000-0001-7847-9320], Apollo - University of Cambridge Repository, Emory University School of Medicine, Emory University [Atlanta, GA], University of Cambridge [UK] (CAM), NHS Foundation Trust [London], The Royal Marsden, University College of London [London] (UCL), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), 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, University of Ottawa [Ottawa], eXYSTAT [Malakoff], Hôpital Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), 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), HAL-SU, Gestionnaire, University of California (UC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Newman N.J., Yu-Wai-Man P., Carelli V., Biousse V., Moster M.L., Vignal-Clermont C., Sergott R.C., Klopstock T., Sadun A.A., Girmens J.-F., La Morgia C., DeBusk A.A., Jurkute N., Priglinger C., Karanjia R., Josse C., Salzmann J., Montestruc F., Roux M., Taiel M., and Sahel J.-A.

Subjects
medicine.medical_specialty, LEBER HEREDITARY OPTIC NEUROPATHY, Visual acuity, Neurology, genetic structures, visual acuity, Genetic enhancement, 03 medical and health sciences, 0302 clinical medicine, Ophthalmology, Medicine, In patient, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ddc:610, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, RC346-429, Original Research, business.industry, gene therapy, eye diseases, Indirect comparison, Natural history, Clinical trial, ND4, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, natural history, 030221 ophthalmology & optometry, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology. Diseases of the nervous system, Neurology (clinical), sense organs, medicine.symptom, business, Leber hereditary optic neuropathy, 030217 neurology & neurosurgery
Abstract

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.Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

Published
2021
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8. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy

Author

Günther Rudolph, Magali Taiel, Laure Blouin, Nancy J. Newman, Rustum Karanjia, Catherine Vignal-Clermont, Thomas Klopstock, Serge Picaud, Robert C. Sergott, Valérie Biousse, Gerard Smits, Caroline Chevalier, Mark L. Moster, Valerio Carelli, Chiara La Morgia, Alfredo A. Sadun, Harvey Masonson, Patrick Yu-Wai-Man, Barrett Katz, David J. Calkins, Yordak Salermo, Pierre Burguière, José-Alain Sahel, University of Cambridge [UK] (CAM), Emory University School of Medicine, Emory University [Atlanta, GA], University of Bologna, Jefferson (Philadelphia University + Thomas Jefferson University), University of California [Los Angeles] (UCLA), University of California, Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Ludwig Maximilian University [Munich] (LMU), University of Ottawa [Ottawa], GenSight Biologics, 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), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], 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), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), HAL-SU, Gestionnaire, University of Bologna/Università di Bologna, University of California (UC), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Centre d'investigation clinique Quinze-Vingts [CHNO] (CIC1423 - CIC QUINZE-VINGTS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Yu-Wai-Man P., Newman N.J., Carelli V., Moster M.L., Biousse V., Sadun A.A., Klopstock T., Vignal-Clermont C., Sergott R.C., Rudolph G., la Morgia C., Karanjia R., Taiel M., Blouin L., Burguiere P., Smits G., Chevalier C., Masonson H., Salermo Y., Katz B., Picaud S., Calkins D.J., Sahel J.-A., Yu Wai Man, Patrick [0000-0001-7847-9320], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, medicine.medical_specialty, Visual acuity, genetic structures, Genetic enhancement, Visual Acuity, Phases of clinical research, Optic Atrophy, Hereditary, Leber, therapy [Optic Atrophy, Hereditary, Leber], visual improvement, law.invention, genetics [Dependovirus], 03 medical and health sciences, LHON, 0302 clinical medicine, Randomized controlled trial, Leber's hereditary optic neuropathy, law, Ophthalmology, medicine, Clinical endpoint, Animals, Retina, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, NADH Dehydrogenase, General Medicine, Genetic Therapy, Dependovirus, medicine.disease, gene therapy, eye diseases, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, genetics [Optic Atrophy, Hereditary, Leber], Optic nerve, ddc:500, sense organs, medicine.symptom, Visual Fields, business, genetics [NADH Dehydrogenase], 030217 neurology & neurosurgery, Tomography, Optical Coherence, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; 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.

Published
2020
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