Cross-Sectional Analysis of Baseline Visual Parameters in Subjects Recruited Into the RESCUE and REVERSE ND4-LHON Gene Therapy Studies.
Adolescent
Adult
Aged
Cross-Sectional Studies
DNA, Mitochondrial
/ genetics
Double-Blind Method
Female
Genetic Therapy
/ methods
Humans
Male
Middle Aged
Optic Atrophy, Hereditary, Leber
/ genetics
Retinal Ganglion Cells
/ pathology
Tomography, Optical Coherence
/ methods
Visual Acuity
Visual Fields
/ physiology
Young Adult
Journal
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
ISSN: 1536-5166
Titre abrégé: J Neuroophthalmol
Pays: United States
ID NLM: 9431308
Informations de publication
Date de publication:
01 Sep 2021
01 Sep 2021
Historique:
pubmed:
27
7
2021
medline:
8
1
2022
entrez:
26
7
2021
Statut:
ppublish
Résumé
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. 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). 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). LHON progresses rapidly in the first months following onset during the subacute phase, followed by relative stabilization during the dynamic phase.
Identifiants
pubmed: 34310464
doi: 10.1097/WNO.0000000000001316
pii: 00041327-202109000-00004
pmc: PMC8366757
doi:
Substances chimiques
DNA, Mitochondrial
0
Types de publication
Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
298-308Subventions
Organisme : Medical Research Council
ID : G0701386
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1002570
Pays : United Kingdom
Organisme : NEI NIH HHS
ID : P30 EY006360
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the North American Neuro-Opthalmology Society.
Références
Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ II, Nikoskelainen EK. Mitochondrial DNA mutation associated with leber's hereditary optic neuropathy. Science. 1988;242:1427–1430.
Carelli V, Carbonelli M, de Coo IF, Kawasaki A, Klopstock T, Lagrèze WA, La Morgia C, Newman NJ, Orssaud C, Pott JWR, Sadun AA, van Everdingen J, Vignal-Clermont C, Votruba M, Yu-Wai-Man P, Barboni P. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J Neuroophthalmol. 2017;37:371–381.
Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies - disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011;30:81–114.
Yu-Wai-Man P, Votruba M, Burté F, La Morgia C, Barboni P, Carelli V. A neurodegenerative perspective on mitochondrial optic neuropathies. Acta Neuropathol. 2016;132:789–806.
Yu-Wai-Man P, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The epidemiology of Leber hereditary optic neuropathy in the north east of England. Am J Hum Genet. 2003;72:333–339.
Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol. 1991;111:750–762.
Puomila A, Hämäläinen P, Kivioja S, Savontaus ML, Koivumäki S, Huoponen K, Nikoskelainen E. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet. 2007;15:1079–1089.
Mascialino B, Leinonen M, Meier T. Meta-analysis of the prevalence of Leber hereditary optic neuropathy mtDNA mutations in Europe. Eur J Ophthalmol. 2012;22:461–465.
Newman NJ, Carelli V, Taiel M, Yu-Wai-Man P. Visual outcomes in leber hereditary optic neuropathy patients with the m.11778G>A (MTND4) mitochondrial DNA mutation. J Neuro Ophthalmol. 2020;40:547–557.
Jurkute N, Harvey J, Yu-Wai-Man P. Treatment strategies for Leber hereditary optic neuropathy. Curr Opin Neurol. 2019;32:99–104.
Guy J, Qi X, Pallotti F, Schon EA, Manfredi G, Carelli V, Martinuzzi A, Hauswirth WW, Lewin AS. Rescue of a mitochondrial deficiency causing leber hereditary optic neuropathy. Ann Neurol. 2002;52:534–542.
Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, Corral-Debrinski M. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet. 2008;83:373–387.
Cwerman-Thibault H, Augustin S, Lechauve C, Ayache J, Ellouze S, Sahel JA, Corral-Debrinski M. Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss. Mol Ther Methods Clin Dev. 2015;2:15003.
Vignal C, Uretsky S, Fitoussi S, Galy A, Blouin L, Girmens JF, Bidot S, Thomasson N, Bouquet C, Valero S, Meunier S, Combal JP, Gilly B, Katz B, Sahel JA. Safety of rAAV2/2- ND4 gene therapy for leber hereditary optic neuropathy. Ophthalmology. 2018;125:945–947.
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 JA; LHON Study Group. Efficacy and safety of intravitreal gene therapy for leber hereditary optic neuropathy treated within 6 Months of disease onset. Ophthalmology. 2021:S0161-6420(20)31187-8.
Yu-Wai-Man P, Newman NJ, Carelli V, Moster ML, Biousse V, Sadun AA, Klopstock T, Vignal-Clermont C, Sergott RC, Rudolph G, La Morgia C, Karanjia R, Taiel M, Blouin L, Burguière P, Smits G, Chevalier C, Masonson H, Salermo Y, Katz B, Picaud S, Calkins DJ, Sahel JA. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. Sci Transl Med. 2020;12:eaaz7423.
Damiani E, Yuecel R, Wallace HM. Repurposing of idebenone as a potential anti-cancer agent. Biochem J. 2019;476:245–259.
Karanjia R, Hwang TJ, Chen AF, Pouw A, Tian JJ, Chu ER, Wang MY, Tran JS, Sadun AA. Correcting finger counting to snellen acuity. Neuroophthalmology. 2016;40:219–221.
Pelli DG, Robson JG, Wilkins AJ. The design of a new letter chart for measuring contrast sensitivity. Clin Vis Sci. 1988;2:187–199.
Mäntyjärvi M, Laitinen T. Normal values for the Pelli-Robson contrast sensitivity test. J Cataract Refract Surg. 2001;27:261–266.
Barboni P, Savini G, Valentino ML, Montagna P, Cortelli P, De Negri AM, Sadun F, Bianchi S, Longanesi L, Zanini M, de Vivo A, Carelli V. Retinal nerve fiber layer evaluation by optical coherence tomography in leber's hereditary optic neuropathy. Ophthalmology. 2005;112:120–126.
Barboni P, Carbonelli M, Savini G, Ramos Cdo V, Carta A, Berezovsky A, Salomao SR, Carelli V, Sadun AA. Natural history of Leber's hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology. 2010;117:623–627.
Balducci N, Savini G, Cascavilla ML, La Morgia C, Triolo G, Giglio R, Carbonelli M, Parisi V, Sadun AA, Bandello F, Carelli V, Barboni P. Macular nerve fibre and ganglion cell layer changes in acute Leber's hereditary optic neuropathy. Br J Ophthalmol. 2016;100:1232–1237.
Moster SJ, Moster ML, Scannell Bryan M, Sergott RC. Retinal ganglion cell and inner plexiform layer loss correlate with visual acuity loss in LHON: a longitudinal, segmentation OCT analysis. Invest Ophthalmol Vis Sci. 2016;57:3872–3883.
Hw Hwang TJ, Karanjia R, Moraes-Filho MN, Gale J, Tran JS, Chu ER, Salomao SR, Berezovsky A, Belfort R Jr, Moraes MN, Sadun F, DeNegri AM, La Morgia C, Barboni P, Ramos CDVF, Chicani CF, Quiros PA, Carelli V, Sadun AA. Natural history of conversion of leber's hereditary optic neuropathy: a prospective case series. Ophthalmology. 2017;124:843–850.
Nikoskelainen EK, Huoponen K, Juvonen V, Lamminen T, Nummelin K, Savontaus M-L. Ophthalmologic findings in leber hereditary optic neuropathy, with special reference to mtDNA mutations. Ophthalmology. 1996;103:504–514.
Sadun F, De Negri AM, Carelli V, Salomao SR, Berezovsky A, Andrade R, Moraes M, Passos A, Belfort R, da Rosa AB, Quiros P, Sadun AA. Ophthalmologic findings in a large pedigree of 11778/Haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol. 2004;137:271–277.