RPE65-Associated Retinal Dystrophies: Phenotypes and Treatment Effects with Voretigene Neparvovec

Katarina Stingl; Claudia Priglinger; Philipp Herrmann

doi:10.1055/a-2227-3671

Klinische Monatsblätter für Augenheilkunde, Table of Contents

Klin Monbl Augenheilkd 2024; 241(03): 259-265
DOI: 10.1055/a-2227-3671

Übersicht

RPE65-Associated Retinal Dystrophies: Phenotypes and Treatment Effects with Voretigene Neparvovec

RPE65 assoziierte Netzhautdystrophien: Phänotypen und Therapieeffekte mit Voretigen Neparvovec

Katarina Stingl ‡

¹University Eye Hospital, Center for Ophthalmology, University of Tübingen, Germany

,

Claudia Priglinger ‡

²Department of Ophthalmology, Ludwig-Maximilians-University Hospital, LMU Munich, Germany

,

Philipp Herrmann

³University Eye Hospital Bonn, University Hospital Bonn, Germany

› Author Affiliations

Abstract

Retinal dystrophies linked to the RPE65 gene are mostly fast-progressing retinal diseases, with childhood onset of night blindness and progressive visual loss up to the middle adult age. Rare phenotypes linked to this gene are known with congenital stationary night blindness or slowly progressing retinitis pigmentosa, as well as an autosomal dominant c.1430A>G (p.Asp477Gly) variant. This review gives an overview of the current knowledge of the clinical phenotypes, as well as experience with the efficacy and safety of the approved gene augmentation therapy voretigene neparvovec.

Zusammenfassung

Netzhautdystrophien durch Mutationen im Gen RPE65 sind meistens schnell fortschreitende Netzhauterkrankungen mit Erstmanifestation im Kindesalter und progredientem Sehverlust im mittleren Lebensalter. Seltene RPE65-Phänotypen sind ebenfalls bekannt, wie kongenitale stationäre Nachtblindheit oder langsam fortschreitende Retinitis pigmentosa, sowie die autosomal-dominante Variante c.1430A>G (p.Asp477Gly). Der Übersichtsartikel beschreibt das aktuelle Wissen um diese Krankheitsbilder sowie die klinischen Erfahrungen mit Wirksamkeit und Sicherheit der zugelassenen Gentherapie Voretigen Neparvovec.

Key words

retinal dystrophy - retinitis pigmentosa - voretigene neparvovec - genotype-phenotype correlation - RPE65 - gene therapy

Schlüsselwörter

Netzhautdystrophie - Voretigen Neparvovec - Gentherapie - RPE65 - Genotyp-Phänotyp-Korrelation - Retinitis pigmentosa

Full Text

References

References
1 Hamel CP, Tsilou E, Pfeffer BA. et al. Molecular cloning and expression of RPE65, a novel retinal pigment epithelium-specific microsomal protein that is post-transcriptionally regulated in vitro . J Biol Chem 1993; 268: 15751-15757
2 Nicoletti A, Wong DJ, Kawase K. et al. Molecular characterization of the human gene encoding an abundant 61 kDa protein specific to the retinal pigment epithelium. Hum Mol Genet 1995; 4: 641-649
3 Kiser PD. Retinal pigment epithelium 65 kDa protein (RPE65): An update. Prog Retin Eye Res 2022; 88: 101013
4 Gu SM, Thompson DA, Srikumari CR. et al. Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nat Genet 1997; 17: 194-197
5 Thompson DA, Gyurus P, Fleischer LL. et al. Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Invest Ophthalmol Vis Sci 2000; 41: 4293-4299
6 Verbakel SK, van Huet RAC, Boon CJF. et al. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res 2018; 66: 157-186
7 Felius J, Thompson DA, Khan NW. et al. Clinical course and visual function in a family with mutations in the RPE65 gene. Arch Ophthalmol 2002; 120: 55-61
8 Hull S, Holder GE, Robson AG. et al. Preserved visual function in retinal dystrophy due to hypomorphic RPE65 mutations. Br J Ophthalmol 2016; 100: 1499-1505
9 Hull S, Mukherjee R, Holder GE. et al. The clinical features of retinal disease due to a dominant mutation in RPE65 . Mol Vis 2016; 22: 626-635
10 Lorenz B, Poliakov E, Schambeck M. et al. A comprehensive clinical and biochemical functional study of a novel RPE65 hypomorphic mutation. Invest Ophthalmol Vis Sci 2008; 49: 5235-5242
11 Schatz P, Preising M, Lorenz B. et al. Fundus albipunctatus associated with compound heterozygous mutations in RPE65 . Ophthalmology 2011; 118: 888-894
12 Kiang AS, Kenna PF, Humphries MM. et al. Properties and Therapeutic Implications of an Enigmatic D477 G RPE65 Variant Associated with Autosomal Dominant Retinitis Pigmentosa. Genes (Basel) 2020; 11: 1420
13 Maguire AM, Russell S, Wellman JA. et al. Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials. Ophthalmology 2019; 126: 1273-1285
14 Russell S, Bennett J, Wellman JA. et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 2017; 390: 849-860
15 Chung DC, Bertelsen M, Lorenz B. et al. The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene. Am J Ophthalmol 2019; 199: 58-70
16 Jacobson SG, Aleman TS, Cideciyan AV. et al. Defining the residual vision in leber congenital amaurosis caused by RPE65 mutations. Invest Ophthalmol Vis Sci 2009; 50: 2368-2375
17 Jacobson SG, Cideciyan AV, Aleman TS. et al. Photoreceptor layer topography in children with leber congenital amaurosis caused by RPE65 mutations. Invest Ophthalmol Vis Sci 2008; 49: 4573-4577
18 Paunescu K, Wabbels B, Preising MN, Lorenz B. Longitudinal and cross-sectional study of patients with early-onset severe retinal dystrophy associated with RPE65 mutations. Graefes Arch Clin Exp Ophthalmol 2005; 243: 417-426
19 Testa F, Murro V, Signorini S. et al. RPE65-Associated Retinopathies in the Italian Population: A Longitudinal Natural History Study. Invest Ophthalmol Vis Sci 2022; 63: 13
20 Social Security Administration (SSA). Disability evaluation under social security: special senses and speed – Adult. Accessed December 22, 2023 at: https://www.ssa.gov/disability/professionals/bluebook/2.00-SpecialSensesandSpeech-Adult.htm
21 Jacobson SG, Aleman TS, Cideciyan AV. et al. Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success. Proc Natl Acad Sci U S A 2005; 102: 6177-6182
22 Lorenz B, Wabbels B, Wegscheider E. et al. Lack of fundus autofluorescence to 488 nanometers from childhood on in patients with early-onset severe retinal dystrophy associated with mutations in RPE65 . Ophthalmology 2004; 111: 1585-1594
23 Chen Y, Moiseyev G, Takahashi Y, Ma JX. RPE65 gene delivery restores isomerohydrolase activity and prevents early cone loss in Rpe65-/- mice. Invest Ophthalmol Vis Sci 2006; 47: 1177-1184
24 Redmond TM, Poliakov E, Yu S. et al. Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proc Natl Acad Sci U S A 2005; 102: 13658-13663
25 Jauregui R, Cho A, Oh JK. et al. Phenotypic expansion of autosomal dominant retinitis pigmentosa associated with the D477 G mutation in RPE65 . Cold Spring Harb Mol Case Stud 2020; 6: a004952
26 Jauregui R, Park KS, Tsang SH. Two-year progression analysis of RPE65 autosomal dominant retinitis pigmentosa. Ophthalmic Genet 2018; 39: 544-549
27 Stingl K, Kempf M, Bartz-Schmidt KU. et al. Spatial and temporal resolution of the photoreceptors rescue dynamics after treatment with voretigene neparvovec. Br J Ophthalmol 2022; 106: 831-838
28 Stingl K, Stingl K, Schwartz H. et al. Full-field Scotopic Threshold Improvement after Voretigene Neparvovec-rzyl Treatment Correlates with Chorioretinal Atrophy. Ophthalmology 2023; 130: 764-770
29 Stingl K, Kempf M, Jung R. et al. Therapy with voretigene neparvovec. How to measure success?. Prog Retin Eye Res 2023; 92: 101115
30 Roman AJ, Schwartz SB, Aleman TS. et al. Quantifying rod photoreceptor-mediated vision in retinal degenerations: dark-adapted thresholds as outcome measures. Exp Eye Res 2005; 80: 259-272
31 Maguire AM, Simonelli F, Pierce EA. et al. Safety and efficacy of gene transfer for Leberʼs congenital amaurosis. N Engl J Med 2008; 358: 2240-2248
32 Testa F, Maguire AM, Rossi S. et al. Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2. Ophthalmology 2013; 120: 1283-1291
33 Bennett J, Wellman J, Marshall KA. et al. Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet 2016; 388: 661-672
34 Gerhardt MJ, Michalakis S, Rudolph G. et al. [RPE65-associated retinal dystrophies: gene therapy preserves vision]. MMW Fortschr Med 2022; 164: 40-41
35 Weleber RG, Pennesi ME, Wilson DJ. et al. Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy. Ophthalmology 2016; 123: 1606-1620
36 Kolesnikova M, Lima de Carvalho jr. JR, Parmann R. et al. Chorioretinal atrophy following voretigene neparvovec despite the presence of fundus autofluorescence. Mol Genet Genomic Med 2022; 10: e2038
37 Levi SR, Oh JK, Lima de Carvalho jr. JR. et al. Quantitative Autofluorescence Following Gene Therapy With Voretigene Neparvovec. JAMA Ophthalmol 2020; 138: 919-921
38 Kortum FC, Kempf M, Jung R. et al. Short term morphological rescue of the fovea after gene therapy with voretigene neparvovec. Acta Ophthalmol 2022; 100: e807-e812
39 Lopez J, Borchert M, Lee TC, Nagiel A. Subretinal deposits in young patients treated with voretigene neparvovec-rzyl for RPE65-mediated retinal dystrophy. Br J Ophthalmol 2023; 107: 299-301
40 Gange WS, Sisk RA, Besirli CG. et al. Perifoveal Chorioretinal Atrophy after Subretinal Voretigene Neparvovec-rzyl for RPE65-Mediated Leber Congenital Amaurosis. Ophthalmol Retina 2022; 6: 58-64
41 Reichel FF, Seitz I, Wozar F. et al. Development of retinal atrophy after subretinal gene therapy with voretigene neparvovec. Br J Ophthalmol 2023; 107: 1331-1335