Voretigene Neparvovec and Gene Therapy for Leber’s Congenital Amaurosis: Review of Evidence to Date

References

• Sahel JA, Marazova K, Audo I. Clinical characteristics and current therapies for inherited retinal degenerations. Cold Spring Harb Perspect Med. 2014;5(2):a017111. doi:10.1101/cshperspect.a017111
   PubMed Web of Science ®Google Scholar
• Cremers FPM, Boon CJF, Bujakowska K, et al. Special issue introduction: inherited retinal disease: novel candidate genes, genotype-phenotype correlations, and inheritance models. Genes (Basel). 2018;9(4):215. doi:10.3390/genes9040215
   PubMed Web of Science ®Google Scholar
• Gregory-Evans K, Pennesi ME, Weleber RG. Retinitis pigmentosa and allied disorders. In: Ryan SJ, editor. Retina. Elsevier; 2013:761–835.
   Google Scholar
• Leber T. Ueber retinitis pigmentosa und angeborene amaurose. Graefes Arch Clin Exp Ophthalmol. 1869;15(3):1–25. doi:10.1007/BF02721213
   Google Scholar
• Perrault I, Rozet JM, Gerber S, et al. Leber congenital amaurosis. Mol Genet Metab. 1999;68(2):200–208. doi:10.1006/mgme.1999.2906
   PubMed Web of Science ®Google Scholar
• Weleber RG, Michaelides M, Trzupek KM, et al. The phenotype of severe early childhood onset retinal dystrophy (SECORD) from mutation of RPE65 and differentiation from leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2011;52(1):292–302. doi:10.1167/iovs.10-6106
   PubMed Web of Science ®Google Scholar
• Anderson WF, Blaese RM, Culver K. The ADA human gene therapy clinical protocol: points to consider response with clinical protocol. Hum Gene Ther. 1990;1(3):331–362. doi:10.1089/hum.1990.1.3-331
   PubMed Web of Science ®Google Scholar
• Deakin CT, Alexander IE, Kerridge I. Accepting risk in clinical research: is the gene therapy field becoming too risk-averse? Mol Ther. 2009;17(11):1842–1848. doi:10.1038/mt.2009.223
   PubMed Web of Science ®Google Scholar
• Bank A. Human somatic cell gene therapy. Bioessays. 1996;18(12):999–1007. doi:10.1002/bies.950181210
   Web of Science ®Google Scholar
• Mathews QL, Curiel DT. Gene therapy: human germline genetics modifications-assessing the scientific, socioethical, and religious issues. South Med J. 2007;100(1):98–100. doi:10.1097/SMJ.0b013e31802e645f
   Web of Science ®Google Scholar
• Gonçalves GAR, Paiva RMA. Gene therapy: advances, challenges and perspectives. Einstein (Sao Paulo). 2017;15(3):369–375. doi:10.1590/S1679-45082017RB4024
   PubMed Web of Science ®Google Scholar
• Zeng Y, Takada Y, Kjellstrom S, et al. RS-1 gene delivery to an adult Rs1h knockout mouse model restores ERG b-wave with reversal of the electronegative waveform of X-linked retinoschisis. Investig Ophthalmol Vis Sci. 2004;45(9):3279–3285. doi:10.1167/iovs.04-0576
   PubMed Web of Science ®Google Scholar
• Han Z, Conley SM, Naash MI. Gene therapy for stargardt disease associated with ABCA4 gene. Adv Exp Med Biol. 2014;801:719–724.
   PubMed Web of Science ®Google Scholar
• Cashman SM, Gracias J, Adhi M, Kumar-Singh R. Adenovirus-mediated delivery of factor H attenuates complement C3 induced pathology in the murine retina: a potential gene therapy for age-related macular degeneration. J Gene Med. 2015;17(10–12):229–243. doi:10.1002/jgm.2865
   Web of Science ®Google Scholar
• Matet A, Kostic C, Bemelmans AP, et al. Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates. Transl Res. 2017;188:40–57. doi:10.1016/j.trsl.2017.06.012
   Web of Science ®Google Scholar
• FDA. FDA Briefing Document: Advisory Committee Meeting. October 12, 2017. BLA 125610 (Voretigene Neparvovec). FDA; 2017.
   Google Scholar
• Hampson G, Towse A, Pearson SD, Dreitlein WB, Henshall C. Gene therapy: evidence, value and affordability in the US health care system. J Comp Eff Res. 2017;7(1):15–28. doi:10.2217/cer-2017-0068
   Web of Science ®Google Scholar
• Takkar B, Bansal P, Venkatesh P. Leber’s congenital amaurosis and gene therapy. Indian J Pediatr. 2018;85(3):237–242. doi:10.1007/s12098-017-2394-1
   PubMed Web of Science ®Google Scholar
• Perrault I, Rozet JM, Gerber S, et al. Spectrum of retGC1 mutations in Leber’s congenital amaurosis. Eur J Hum Genet. 2000;8(8):578–582. doi:10.1038/sj.ejhg.5200503
   Web of Science ®Google Scholar
• Wimberg H, Lev D, Yosovich K, et al. Photoreceptor guanylate cyclase (GUCY2D) mutations cause retinal dystrophies by severe malfunction of Ca2+-dependent cyclic GMP synthesis. Front Mol Neurosci. 2018;11:348. doi:10.3389/fnmol.2018.00348
   Web of Science ®Google Scholar
• Jacobson SG, Cideciyan AV, Peshenko IV, et al. Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants. Hum Mol Genet. 2013;22(1):168–183. doi:10.1093/hmg/dds421
   PubMed Web of Science ®Google Scholar
• Boye SE. Leber congenital amaurosis caused by mutations in GUCY2D. Cold Spring Harb Perspect Med. 2014;5(1):a017350. doi:10.1101/cshperspect.a017350
   Web of Science ®Google Scholar
• Haire SE, Pang J, Boye SL, et al. Light-driven cone arrestin translocation in cones of postnatal guanylate cyclase-1 knockout mouse retina treated with AAV-GC1. Invest Ophthalmol Vis Sci. 2006;47(9):3745–3753. doi:10.1167/iovs.06-0086
   PubMed Web of Science ®Google Scholar
• Mihelec M, Pearson RA, Robbie SJ, et al. Long-term preservation of cones and improvement in visual function following gene therapy in a mouse model of leber congenital amaurosis caused by guanylate cyclase-1 deficiency. Hum Gene Ther. 2011;22(10):1179–1190. doi:10.1089/hum.2011.069
   PubMed Web of Science ®Google Scholar
• Boye SE, Boye SL, Pang J, et al. Functional and behavioral restoration of vision by gene therapy in the guanylate cyclase-1 (GC1) knockout mouse. PLoS One. 2010;5(6):e11306. doi:10.1371/journal.pone.0011306
   PubMed Web of Science ®Google Scholar
• Hidalgo-de-Quintana J, Evans RJ, Cheetham ME, et al. The Leber congenital amaurosis protein AIPL1 functions as part of a chaperone heterocomplex. Invest Ophthalmol Vis Sci. 2008;49(7):2878–2887. doi:10.1167/iovs.07-1576
   Web of Science ®Google Scholar
• Sohocki MM, Bowne SJ, Sullivan LS, et al. Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis. Nat Genet. 2000;24(1):79‐83. doi:10.1038/71732
   Web of Science ®Google Scholar
• Liu X, Bulgakov OV, Wen XH, et al. AIPL1, the protein that is defective in Leber congenital amaurosis, is essential for the biosynthesis of retinal rod cGMP phosphodiesterase. Proc Natl Acad Sci U S A. 2004;101(38):13903‐13908. doi:10.1073/pnas.0405160101
   Web of Science ®Google Scholar
• Tan MH, Mackay DS, Cowing J, et al. Leber congenital amaurosis associated with AIPL1: challenges in ascribing disease causation, clinical findings, and implications for gene therapy. PLoS One. 2012;7(3):e32330. doi:10.1371/journal.pone.0032330
   PubMed Web of Science ®Google Scholar
• Dharmaraj S, Leroy BP, Sohocki MM, et al. The phenotype of leber congenital amaurosis in patients with AIPL1 mutations. Arch Ophthalmol. 2004;122(7):1029–1037. doi:10.1001/archopht.122.7.1029
   PubMedGoogle Scholar
• Aboshiha J, Dubis AM, Spuy J, et al. Preserved outer retina in AIPL1 Leber’s congenital amaurosis: implications for gene therapy. Ophthalmology. 2015;122(4):862–864. doi:10.1016/j.ophtha.2014.11.019
   PubMed Web of Science ®Google Scholar
• Testa F, Surace EM, Rossi S, et al. Evaluation of Italian patients with leber congenital amaurosis due to AIPL1 mutations highlights the potential applicability of gene therapy. Invest Ophthalmol Vis Sci. 2011;52(8):5618–5624. doi:10.1167/iovs.10-6543
   Web of Science ®Google Scholar
• Dryja TP, Adams SM, Grimsby JL, et al. Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am J Hum Genet. 2001;68(5):1295‐1298. doi:10.1086/320113
   Web of Science ®Google Scholar
• Gerber S, Perrault I, Hanein S, et al. Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis. Eur J Hum Genet. 2001;9(8):561–571. doi:10.1038/sj.ejhg.5200689
   PubMed Web of Science ®Google Scholar
• Li T. Leber congenital amaurosis caused by mutations in RPGRIP1. Cold Spring Harb Perspect Med. 2014;5(4):a017384. doi:10.1101/cshperspect.a017384
   Web of Science ®Google Scholar
• Pawlyk BS, Smith AJ, Buch PK, et al. Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP. Invest Ophthalmol Vis Sci. 2005;46(9):3039–3045. doi:10.1167/iovs.05-0371
   PubMed Web of Science ®Google Scholar
• Pawlyk BS, Bulgakov OV, Liu X, et al. Replacement gene therapy with a human RPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis. Hum Gene Ther. 2010;21:993–1004.
   PubMed Web of Science ®Google Scholar
• Henderson RH, Mackay DS, Li Z, et al. Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1. Br J Ophthalmol. 2011;95:811–817. doi:10.1136/bjo.2010.186882
   PubMed Web of Science ®Google Scholar
• Simonelli F, Ziviello C, Testa F, et al. Clinical and molecular genetics of Leber’s congenital amaurosis: a multicenter study of Italian patients. Invest Ophthalmol Vis Sci. 2007;48(9):4284–4290. doi:10.1167/iovs.07-0068
   PubMed Web of Science ®Google Scholar
• Ahmed Khan S, Richard Nestel A. CRB1 gene mutation causing different phenotypes of leber congenital amaurosis in siblings. J Ophthalmic Vis Res. 2019;14(4):518–524. doi:10.18502/jovr.v14i4.5467
   Web of Science ®Google Scholar
• van de Pavert SA, Kantardzhieva A, Malysheva A, et al. Crumbs homologue 1 is required for maintenance of photoreceptor cell polarization and adhesion during light exposure. J Cell Sci. 2004;117(18):4169. doi:10.1242/jcs.01301
   PubMed Web of Science ®Google Scholar
• Boon N, Wijnholds J, Pellissier LP. Research models and gene augmentation therapy for CRB1 retinal dystrophies. Front Neurosci. 2020;14:860. doi:10.3389/fnins.2020.00860
   Web of Science ®Google Scholar
• den Hollander AI, Koenekoop RK, Yzer S, et al. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet. 2006;79(3):556–561. doi:10.1086/507318
   PubMed Web of Science ®Google Scholar
• Perrault I, Delphin N, Hanein S, et al. Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat. 2007;28(4):416. doi:10.1002/humu.9485
   PubMedGoogle Scholar
• McAnany JJ, Genead MA, Walia S, et al. Visual acuity changes in patients with leber congenital amaurosis and mutations in CEP290. JAMA Ophthalmol. 2013;131(2):178–182. doi:10.1001/2013.jamaophthalmol.354
   PubMed Web of Science ®Google Scholar
• Yzer S, Hollander AI, Lopez I, et al. Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290. Mol Vis. 2012;18:412‐425.
   Web of Science ®Google Scholar
• Cideciyan AV, Rachel RA, Aleman TS, et al. Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. Hum Mol Genet. 2011;20(7):1411–1423. doi:10.1093/hmg/ddr022
   PubMed Web of Science ®Google Scholar
• Kong J, Kim S-R, Binley K, et al. Correction of the disease phenotype in the mouse model of stargardt disease by lentiviral gene therapy. Gene Ther. 2008;15(19):1311–1320. doi:10.1038/gt.2008.78
   PubMed Web of Science ®Google Scholar
• Verrier JD, Madorsky I, Coggin WE, et al. Bicistronic lentiviruses containing a viral 2A cleavage sequence reliably co-express two proteins and restore vision to an animal model of LCA1. PLoS One. 2011;6(5):e20553. doi:10.1371/journal.pone.0020553
   Web of Science ®Google Scholar
• den Hollander AI, Roepman R, Koenekoop RK, et al. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res. 2008;27(4):391–419. doi:10.1016/j.preteyeres.2008.05.003
   PubMed Web of Science ®Google Scholar
• Mackay DS, Dev Borman A, Moradi P, et al. RDH12 retinopathy: novel mutations and phenotypic description. Mol Vis. 2011;17:2706–2716.
   PubMed Web of Science ®Google Scholar
• Parker RO, Crouch RK. Dehydrogenases RDHs in the visual cycle. Exp Eye Res. 2010;91(6):788–792. doi:10.1016/j.exer.2010.08.013
   PubMed Web of Science ®Google Scholar
• Haeseleer F, Jang GF, Imanishi Y, et al. Dual-substrate specificity short chain retinol dehydrogenases from the vertebrate retina. J Biol Chem. 2002;277(47):45537‐45546. doi:10.1074/jbc.M208882200
   Web of Science ®Google Scholar
• Schuster A, Janecke AR, Wilke R, et al. The phenotype of early-onset retinal degeneration in persons with RDH12 mutations. Invest Ophthalmol Vis Sci. 2007;48(4):1824–1831. doi:10.1167/iovs.06-0628
   PubMed Web of Science ®Google Scholar
• Valverde D, Pereiro I, Vallespín E, et al. Complexity of phenotype–genotype correlations in Spanish patients with RDH12 mutations. Invest Ophthalmol Vis Sci. 2009;50(3):1065–1068. doi:10.1167/iovs.08-2083
   Web of Science ®Google Scholar
• Thompson DA, Jia L, Yao J, et al. AAV-mediated expression of human Rdh12 in mouse retina. Invest Ophthalmol Vis Sci. 2012;53:1916.
   Google Scholar
• Shahi PK, Hermans D, Sinha D, et al. Gene augmentation and readthrough rescue channelopathy in an iPSC-RPE model of congenital blindness. Am J Hum Genet. 2019;104(2):310–318. doi:10.1016/j.ajhg.2018.12.019
   PubMed Web of Science ®Google Scholar
• Pattnaik BR, Shahi PK, Marino MJ, et al. A novel KCNJ13 nonsense mutation and loss of Kir7.1 channel function causes leber congenital amaurosis (LCA16). Hum Mutat. 2015;36(7):720–727. doi:10.1002/humu.22807
   PubMed Web of Science ®Google Scholar
• Khan AO, Bergmann C, Neuhaus C, Bolz HJ. A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations. Ophthalmic Genet. 2015;36(1):79–84. doi:10.3109/13816810.2014.985846
   PubMed Web of Science ®Google Scholar
• 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(38):13658‐13663. doi:10.1073/pnas.0504167102
   Web of Science ®Google Scholar
• Hanein S, Perrault I, Gerber S, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum Mutat. 2004;23(4):306–317. doi:10.1002/humu.20010
   PubMed Web of Science ®Google Scholar
• Dev Borman A, Ocaka LA, Mackay DS, et al. Early onset retinal dystrophy due to mutations in LRAT: molecular analysis and detailed phenotypic study. Invest Ophthalmol Vis Sci. 2012;53(7):3927–3938. doi:10.1167/iovs.12-9548
   PubMed Web of Science ®Google Scholar
• Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001;28(1):92–95. doi:10.1038/ng0501-92
   PubMed Web of Science ®Google Scholar
• Cideciyan AV, Jacobson SG, Beltran WA, et al. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A. 2013;110(6):E517–E525. doi:10.1073/pnas.1218933110
   PubMed Web of Science ®Google Scholar
• Swain G, Prociuk M, Bagel J, et al. Adeno-associated virus serotypes 9 and rh10 mediate strong neuronal transduction of the dog brain. Gene Ther. 2014;21(1):28–36. doi:10.1038/gt.2013.54
   PubMed Web of Science ®Google Scholar
• Narfstrom K, Katz ML, Bragadottir R, et al. Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog. Invest Ophthalmol Vis Sci. 2003;44(4):1663–1672. doi:10.1167/iovs.02-0595
   PubMed Web of Science ®Google Scholar
• Narfstrom K, Katz ML, Ford M, et al. In vivo gene therapy in young and adult RPE65-/- dogs produces long-term visual improvement. J Hered. 2003;94(1):31–37. doi:10.1093/jhered/esg015
   PubMed Web of Science ®Google Scholar
• Acland GM, Aguirre GD, Bennett J, et al. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther. 2005;12(6):1072–1082. doi:10.1016/j.ymthe.2005.08.008
   PubMed Web of Science ®Google Scholar
• Le Meur G, Stieger K, Smith AJ, et al. Restoration of vision in RPE65-deficient briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther. 2007;14(4):292–303. doi:10.1038/sj.gt.3302861
   PubMed Web of Science ®Google Scholar
• Annear MJ, Bartoe JT, Barker SE, et al. Gene therapy in the second eye of RPE65-deficient dogs improves retinal function. Gene Ther. 2011;18(1):53–61. doi:10.1038/gt.2010.111
   Web of Science ®Google Scholar
• Wright JF. Manufacturing and characterizing AAV-based vectors for use in clinical studies. Gene Ther. 2008;15(11):840–848. doi:10.1038/gt.2008.65
   Web of Science ®Google Scholar
• 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(17):6177–6182. doi:10.1073/pnas.0500646102
   PubMed Web of Science ®Google Scholar
• Narfström K, Seeliger M, Lai CM, et al. Morphological aspects related to long-term functional improvement of the retina in the 4 years following rAAV-mediated gene transfer in the RPE65 null mutation dog. Adv Exp Med Biol. 2008;613:139–146. doi:10.1007/978-0-387-74904-4_15
   Web of Science ®Google Scholar
• Kumaran N, Moore AT, Weleber RG, et al. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. Br J Ophthalmol. 2017;101(9):1147–1154. doi:10.1136/bjophthalmol-2016-309975
   PubMed Web of Science ®Google Scholar
• Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2231–2239. doi:10.1056/NEJMoa0802268
   PubMed Web of Science ®Google Scholar
• Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2240–2248. doi:10.1056/NEJMoa0802315
   PubMed Web of Science ®Google Scholar
• Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19(10):979–990. doi:10.1089/hum.2008.107
   PubMed Web of Science ®Google Scholar
• Miyazaki J, Takaki S, Araki K, et al. Expression vector system based on the chicken beta-actin promoter directs efficient production of interleukin-5. Gene. 1989;79(2):269–277. doi:10.1016/0378-1119(89)90209-6
   Web of Science ®Google Scholar
• Annear MJ, Mowat FM, Bartoe JT, et al. Successful gene therapy in older Rpe65-deficient dogs following subretinal injection of an adeno-associated vector expressing RPE65. Hum Gene Ther. 2013;24(10):883–893. doi:10.1089/hum.2013.146
   PubMed Web of Science ®Google Scholar
• Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a Phase 1 dose-escalation trial. Lancet. 2009;374(9701):1597–1605. doi:10.1016/S0140-6736(09)61836-5
   PubMed Web of Science ®Google Scholar
• Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012;130(1):9–24. doi:10.1001/archophthalmol.2011.298
   PubMed Web of Science ®Google Scholar
• 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(6):1283–1291. doi:10.1016/j.ophtha.2012.11.048
   PubMed Web of Science ®Google Scholar
• Cideciyan AV, Hauswirth WW, Aleman TS, et al. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther. 2009;20(9):999–1004. doi:10.1089/hum.2009.086
   PubMed Web of Science ®Google Scholar
• Wojno AP, Pierce EA, Bennett J. Seeing the light. Sci Transl Med. 2013;5(175):175–178. doi:10.1126/scitranslmed.3005798
   Web of Science ®Google Scholar
• Yavuz B, Kompella UB. Ocular drug delivery. Handb Exp Pharmacol. 2017;242:57–93.
   PubMedGoogle Scholar
• Patel A, Cholkar K, Agrahari V, et al. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2(2):47–64. doi:10.5497/wjp.v2.i2.47
   PubMedGoogle Scholar
• Maia M, Kellner L, de Juan E Jr, et al. Effects of indocyanine green injection on the retinal surface and into the subretinal space in rabbits. Retina. 2004;24:80–91. doi:10.1097/00006982-200402000-00012
   PubMed Web of Science ®Google Scholar
• Stout JT, Francis PJ. Surgical approaches to gene and stem cell therapy for retinal disease. Hum Gene Ther. 2011;22(5):531–535. doi:10.1089/hum.2011.060
   Web of Science ®Google Scholar
• Qi Y, Dai X, Zhang H, et al. Trans-corneal subretinal injection in mice and its effect on the function and morphology of the retina. PLoS One. 2015;10(8):e0136523. doi:10.1371/journal.pone.0136523
   Web of Science ®Google Scholar
• Ehlers JP, Petkovsek DS, Yuan A, et al. Intrasurgical assessment of subretinal tPA injection for submacular hemorrhage in the PIONEER study utilizing intraoperative OCT. Ophthalmic Surg Lasers Imaging Retina. 2015;46(3):327–332. doi:10.3928/23258160-20150323-05
   PubMed Web of Science ®Google Scholar
• Parikh S, Le A, Davenport J, et al. An alternative and validated injection method for accessing the subretinal space via a transcleral posterior approach. J Vis Exp. 2016;7(118):e54808. doi:10.3791/54808
   Web of Science ®Google Scholar
• Georgiadis A, Duran Y, Ribeiro J, et al. Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65. Gene Ther. 2016;23(12):857–862. doi:10.1038/gt.2016.66
   PubMed Web of Science ®Google Scholar
• Weber M, Rabinowitz J, Provost N, et al. Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery. Mol Ther. 2003;7(6):774–781. doi:10.1016/S1525-0016(03)00098-4
   Web of Science ®Google Scholar
• Jacobson SG, Acland GM, Aguirre GD, et al. Safety of recombinant adeno-associated virus type 2- RPE65 vector delivered by ocular subretinal injection. Mol Ther. 2006;13(6):1074–1084. doi:10.1016/j.ymthe.2006.03.005
   PubMed Web of Science ®Google Scholar
• Boye SE, Boye SL, Lewin AS, Hauswirth WW. A comprehensive review of retinal gene therapy. Mol Ther. 2013;21(3):509–519. doi:10.1038/mt.2012.280
   PubMed Web of Science ®Google Scholar
• Kansara V, Muya L, Wan CR, Ciulla TA. Suprachoroidal delivery of viral and nonviral gene therapy for retinal diseases. J Ocul Pharmacol Ther. 2020;36(6):384–392. doi:10.1089/jop.2019.0126
   PubMed Web of Science ®Google Scholar
• Choi VW, McCarty DM, Samulski RJ. Host cell DNA repair pathways in adeno-associated viral genome processing. J Virol. 2006;80(21):10346–10356. doi:10.1128/JVI.00841-06
   PubMed Web of Science ®Google Scholar
• Dong B, Nakai H, Xiao W. Characterization of genome integrity for oversized recombinant AAV vector. Mol Ther. 2010;18(1):87–92. doi:10.1038/mt.2009.258
   PubMed Web of Science ®Google Scholar
• Wu Z, Yang H, Colosi P. Effect of genome size on AAV vector packaging. Mol Ther. 2010;18(1):80–86. doi:10.1038/mt.2009.255
   PubMed Web of Science ®Google Scholar
• McCarty DM, Monahan PE, Samulski RJ. Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther. 2001;8(16):1248–1254. doi:10.1038/sj.gt.3301514
   PubMed Web of Science ®Google Scholar
• McCarty DM. Self-complementary AAV vectors; advances and applications. Mol Ther. 2008;16(10):1648–1656. doi:10.1038/mt.2008.171
   PubMed Web of Science ®Google Scholar
• Koilkonda RD, Chou T-H, Porciatti V, Hauswirth WW, Guy J. Induction of rapid and highly efficient expression of the human ND4 complex I subunit in the mouse visual system by self-complementary adeno-associated virus. Arch Ophthalmol. 2010;128(7):876–883. doi:10.1001/archophthalmol.2010.135
   Google Scholar
• Petersen-Jones SM, Bartoe JT, Fischer AJ, et al. AAV retinal transduction in a large animal model species: comparison of a self-complementary AAV2/5 with a single-stranded AAV2/5 vector. Mol Vision. 2009;15:1835–1842.
   Web of Science ®Google Scholar
• Natkunarajah M, Trittibach P, McIntosh J, et al. Assessment of ocular transduction using single-stranded and self-complementary recombinant adeno-associated virus serotype 2/8. Gene Ther. 2007;15(6):463–467. doi:10.1038/sj.gt.3303074
   Web of Science ®Google Scholar
• Day TP, Byrne LC, Schaffer DV, Flannery JG. Advances in AAV vector development for gene therapy in the retina. Adv Exp Med Biol. 2014;801:687–693. doi:10.1007/978-1-4614-3209-8_86
   PubMed Web of Science ®Google Scholar
• Rayaprolu V, Kruse S, Kant R, et al. Comparative analysis of adeno-associated virus capsid stability and dynamics. J Virol. 2013;87(24):13150–13160. doi:10.1128/JVI.0141513
   Web of Science ®Google Scholar
• Pang JJ, Chang B, Kumar A, et al. Gene therapy restores vision-dependent behavior as well as retinal structure and function in a mouse model of RPE65 Leber congenital amaurosis. Mol Ther. 2006;13(3):565–572. doi:10.1016/j.ymthe.2005.09.001
   PubMed Web of Science ®Google Scholar
• Buck TM, Wijnholds J. Recombinant adeno-associated viral vectors (rAAV)-vector elements in ocular gene therapy clinical trials and transgene expression and bioactivity assays. Int J Mol Sci. 2020;21(12):4197. doi:10.3390/ijms21124197
   PubMed Web of Science ®Google Scholar
• Jacobson SG, Boye SL, Aleman TS, et al. Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in leber congenital amaurosis. Hum Gene Ther. 2006b;17(8):845–858. doi:10.1089/hum.2006.17.845
   PubMed Web of Science ®Google Scholar
• Pierce EA, Bennett J. The status of RPE65 gene therapy trials: safety and efficacy. Cold Spring Harb Perspect Med. 2015;5(9):a017285. doi:10.1101/cshperspect.a017285
   PubMed Web of Science ®Google Scholar
• Cideciyan AV, Aleman TS, Boye SL, et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci. 2008;105(39):15112–15117. doi:10.1073/pnas.0807027105
   PubMed Web of Science ®Google Scholar
• Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010;18(3):643–650. doi:10.1038/mt.2009.277
   PubMed Web of Science ®Google Scholar
• Ashtari M, Cyckowski LL, Monroe JF, et al. The human visual cortex responds to gene therapy-mediated recovery of retinal function. J Clin Invest. 2011;121(6):2160–2168. doi:10.1172/JCI57377
   PubMed Web of Science ®Google Scholar
• Banin E, Bandah-Rozenfeld D, Obolensky A, et al. Molecular anthropology meets genetic medicine to treat blindness in the North African Jewish population: human gene therapy initiated in Israel. Hum Gene Ther. 2010;21(12):1749–1757. doi:10.1089/hum.2010.047
   PubMed Web of Science ®Google Scholar
• Le Meur G, Lebranchu P, Billaud F, et al. Safety and long-term efficacy of AAV4 gene therapy in patients with RPE65 leber congenital amaurosis. Mol Ther. 2018;26(1):256–268. doi:10.1016/j.ymthe.2017.09.014
   PubMed Web of Science ®Google Scholar
• Amado D, Mingozzi F, Hui D, et al. Safety and efficacy of subretinal readministration of an AAV2 vector in large animal models: implications for studies in humans. Sci Transl Med. 2010;2(21):21ra16. doi:10.1126/scitranslmed.3000659
   PubMed Web of Science ®Google Scholar
• Bennett J, Ashtari M, Wellman J, et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012;4(120):120ra115. doi:10.1126/scitranslmed.3002865
   Web of Science ®Google Scholar
• 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(10045):661–672. doi:10.1016/S0140-6736(16)30371-3
   PubMed Web of Science ®Google Scholar
• 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(10097):849–860. doi:10.1016/S0140-6736(17)31868-8
   PubMed Web of Science ®Google Scholar
• Darrow JJ. Luxturna: FDA documents reveal the value of a costly gene therapy. Drug Discov Today. 2019;24(4):949–954. doi:10.1016/j.drudis.2019.01.019
   PubMed Web of Science ®Google Scholar
• Chung DC, McCague S, Yu ZF, et al. Novel mobility test to assess functional vision in patients with inherited retinal dystrophies. Clin Exp Ophthalmol. 2018;46(3):247‐259. doi:10.1111/ceo.13022
   Web of Science ®Google Scholar
• Rodrigues GA, Shalaev E, Karami TK, Cunningham J, Slater NKH, Rivers HM. Pharmaceutical development of AAV-based gene therapy products for the eye. Pharm Res. 2018;36(2):29. doi:10.1007/s11095-018-2554-7
   PubMed Web of Science ®Google Scholar
• Novartis announces landmark EU approval for one-time gene therapy Luxturna® to restore vision in people with rare inherited retinal disease [Internet]. Novartis; [cited May 24, 2020]. Available from: https://www.novartis.com/news/media-releases/novartis-announces-landmark-eu-approval-one-time-gene-therapy-luxturna-restore-vision-people-rare-inherited-retinal-disease.
   Google Scholar
• Moiseyev G, Chen Y, Takahashi Y, Wu BX, Ma JX. RPE65 is the isomerohydrolase in the retinoid visual cycle. Proc Nat Acad Sci. 2005;102(35):12413–12418. doi:10.1073/pnas.0503460102
   PubMed Web of Science ®Google Scholar
• Mackay DS, Ocaka LA, Borman AD, et al. Screening of SPATA7 in patients with leber congenital amaurosis and severe childhood-onset retinal dystrophy reveals disease-causing mutations. Invest Ophthal Vis Sci. 2011;52(6):3032–3038. doi:10.1167/iovs.10-7025
   PubMed Web of Science ®Google Scholar
• Li Y, Wang H, Peng J, et al. Mutation survey of known LCA gene and loci in the Saudi Arabian population. Invest Ophthalmol Vis Sci. 2009;50(3):1336–1343. doi:10.1167/iovs.08-2589
   PubMed Web of Science ®Google Scholar
• Boldt K, Mans DA, Won J, et al. Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice. J Clin Invest. 2011;121(6):2169–2180. doi:10.1172/JCI45627
   Web of Science ®Google Scholar
• Dharmaraj S, Li Y, Robitaille JM, et al. A novel locus for Leber congenital amaurosis maps to chromosome 6q. (letter). Am J Hum Genet. 2000;66(1):319–326. doi:10.1086/302719
   Web of Science ®Google Scholar
• Mohamed MD, Topping NC, Jafri H, Raashed Y, McKibbin MA, Inglehearn CF. Progression of phenotype in Leber’s congenital amaurosis with a mutation at the LCA5 locus. Br J Ophthalmol. 2003;87(4):473–475. doi:10.1136/bjo.87.4.473
   Web of Science ®Google Scholar
• Jacobson SG, Cideciyan AV, Huang WC, et al. Leber congenital amaurosis: genotypes and retinal structure phenotypes. Adv Exp Med Biol. 2016;854:169–175.
   PubMed Web of Science ®Google Scholar
• Nichols LL 2nd, Alur RP, Boobalan E, et al. Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL. Hum Mutat. 2010;31(6):E1472–83. doi:10.1002/humu.21268
   PubMed Web of Science ®Google Scholar
• Kimura A, Singh D, Wawrousek EF, Kikuchi M, Nakamura M, Both ST. PCE-1/RX and OTX/CRX interactions are necessary for photoreceptor-specific gene expression. J Biol Chem. 2000;14(275):1152–1160. doi:10.1074/jbc.275.2.1152
   Web of Science ®Google Scholar
• Freund CL, Wang QL, Chen S, et al. De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis. Nat Genet. 1998;18(4):311–312. doi:10.1038/ng0498-311
   PubMed Web of Science ®Google Scholar
• Swaroop A, Wang QL, Wu W, et al. Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function. Hum Mol Genet. 1999;8(2):299–305. doi:10.1093/hmg/8.2.299
   PubMed Web of Science ®Google Scholar
• Akagi T, Mandai M, Ooto S, et al. Otx2 homeobox gene induces photoreceptor-specific phenotypes in cells derived from adult iris and ciliary tissue. Invest Ophthal Vis Sci. 2004;45(12):4570–4575. doi:10.1167/iovs.04-0697
   PubMed Web of Science ®Google Scholar
• Koenekoop RK, Wang H, Majewski J, et al. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nat Genet. 2012;44(9):1035–1039. doi:10.1038/ng.2356
   PubMed Web of Science ®Google Scholar
• Burnight ER, Wiley LA, Drack AV, et al. CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype. Gene Ther. 2014;21(7):662‐672. doi:10.1038/gt.2014.39
   Web of Science ®Google Scholar
• Collart FR, Huberman E. Cloning and sequence analysis of the human and Chinese hamster inosine-5-prime-monophosphate dehydrogenase cDNAs. J Biol Chem. 1988;263:15769–15772.
   PubMed Web of Science ®Google Scholar
• Bowne SJ, Sullivan LS, Mortimer SE, et al. Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and Leber congenital amaurosis. Invest Ophthal Vis Sci. 2006;47(1):34–42. doi:10.1167/iovs.05-0868
   PubMed Web of Science ®Google Scholar
• Molday LL, Djajadi H, Yan P, et al. RD3 gene delivery restores guanylate cyclase localization and rescues photoreceptors in the Rd3 mouse model of Leber congenital amaurosis 12. Hum Mol Genet. 2013;22(19):3894–3905. doi:10.1093/hmg/ddt244
   PubMed Web of Science ®Google Scholar
• Preising MN, Hausotter-Will N, Solbach MC, Friedburg C, Rüschendorf F, Lorenz B. Mutations in RD3 are associated with an extremely rare and severe form of early onset retinal dystrophy. Invest Ophthal Vis Sci. 2012;53(7):3463–3472. doi:10.1167/iovs.12-9519
   Web of Science ®Google Scholar
• Friedman JS, Chang B, Kannabiran C, et al. Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am J Hum Genet. 2006;79(6):1059–1070. doi:10.1086/510021
   PubMed Web of Science ®Google Scholar
• Xi Q, Pauer GJ, Marmorstein AD, Crabb JW, Hagstrom SA. Tubby-like protein 1 (TULP1) interacts with F-actin in photoreceptor cells. Invest Ophthalmol Vis Sci. 2005;46(12):4754–4761. doi:10.1167/iovs.05-0693
   Web of Science ®Google Scholar
• Mataftsi A, Schorderet DF, Chachoua L, et al. Novel TULP1 mutation causing leber congenital amaurosis or early onset retinal degeneration. Invest Ophthalmol Vis Sci. 2007;48(11):5160–5167. doi:10.1167/iovs.06-1013
   PubMed Web of Science ®Google Scholar
• Zhang L, Lim SL, Du H, et al. High temperature requirement factor A1 (HTRA1) gene regulates angiogenesis through transforming growth factor-β family member growth differentiation factor 6. J Biol Chem. 2012;287(2):1520–1526. doi:10.1074/jbc.M111.275990
   Web of Science ®Google Scholar
• Asai-Coakwell M, French CR, Berry KM. GDF6, a novel locus for a spectrum of ocular developmental anomalies. Am J Hum Genet. 2007;80(2):306–315. doi:10.1086/511280
   PubMed Web of Science ®Google Scholar
• The online mendelian inheritance in man website. Available from: www.omim.org. Accessed August 15, 2017. OMIM# 179605. Peripherin 2, Mouse, Homolog of PRPH2. Cytogenetic location.
   Google Scholar
• Bascom RA, Connell G, Garcia-Heras J, et al. Molecular and ultrastructural characterization of the products of the human retinopathy candidate genes ROM1 and RDS. (Abstract). Am J Hum Genet. 1990;47(suppl):A101.
   Google Scholar
• Wang X, Wang H, Sun V, et al. Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing. J Med Genet. 2013;50(10):674–688. doi:10.1136/jmedgenet-2013-101558
   PubMed Web of Science ®Google Scholar