Gene therapies for retinal dystrophies: potential in the Chinese population
Keywords:Choroideremia, Color vision defects, Gene therapy, Leber congenital amaurosis, Night blindness, congenital stationary, Retinitis pigmentosa
Retinal dystrophies (RD) refer to a group of clinically and genetically heterogenous degenerative conditions of the retina. We aim to summarize emerging gene therapies for RD and their efficacy in restoring photoreceptor or bipolar cell functions. In patients with retinitis pigmentosa, injection of adeno-associated virus containing RPE65, RPGR or MERTK results in improvements in outcomes of the multi-luminal mobility test and full-field light sensitivity threshold test. In animal models of congenital stationary night blindness, gene augmentation of Cacn1f, LRIT3 or Nyx increases ON-bipolar cell signaling cascade and preserves retinal morphology. Patients with achromatopsia show improved visual acuity, contrast sensitivity, and cone responses after injection of a vector comprising CNGA3 or CNGB3. In patients with Leber congenital amaurosis, administration of a vector containing RPE65 or RDH12 results in improved full-field sensitivity to white light and photoreceptors responses, particularly in pediatric populations. Some patients have improved dark-adapted spectral sensitivities and pupillary light responses after injection of vectors. For choroideremia, REP1 gene therapy has been shown to improve visual acuity and retinal sensitivity. Nonetheless, voretigene neparvovec-ryzl (Luxturna) remains to be the only approved gene therapy in patients with biallelic RPE65 mutation. In the Chinese population, RPGR, Lrit3, Nyx, CNGA3, RPE65, RDH12, and CHM gene therapies may be beneficial, because the mutated genes are compatible to the genes investigated in previous clinical trials. A thorough understanding of gene therapies for different RD subtypes may allow more personalized management of retinal degeneration.
Ziccardi L, Cordeddu V, Gaddini L, et al. Gene therapy in retinal dystrophies. Int J Mol Sci 2019;20:5722.
Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res 2010;29:335-75.
Nash BM, Wright DC, Grigg JR, Bennetts B, Jamieson RV. Retinal dystrophies, genomic applications in diagnosis and prospects for therapy. Transl Pediatr 2015;4:139-63.
Chaumet-Riffaud AE, Chaumet-Riffaud P, Cariou A, et al. Impact of retinitis pigmentosa on quality of life, mental health, and employment among young adults. Am J Ophthalmol 2017;177:169-74.
Gegenfurtner KR. Cortical mechanisms of colour vision. Nat Rev Neurosci 2003;4:563-72.
Palczewski K, Kiser PD. Shedding new light on the generation of the visual chromophore. Proc Natl Acad Sci U S A 2020;117:19629-38.
Choi EH, Daruwalla A, Suh S, Leinonen H, Palczewski K. Retinoids in the visual cycle: role of the retinal G protein-coupled receptor. J Lipid Res 2021;62:100040.
Patel N, Aldahmesh MA, Alkuraya H, et al. Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies. Genet Med 2016;18:554-62.
Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001;28:92-5.
Lamba DA, Karl MO, Ware CB, Reh TA. Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci U S A 2006;103:12769-74.
Klassen HJ, Ng TF, Kurimoto Y, et al. Multipotent retinal progenitors express developmental markers, differentiate into retinal neurons, and preserve light-mediated behavior. Invest Ophthalmol Vis Sci 2004;45:4167-73.
Bucher K, Rodríguez-Bocanegra E, Dauletbekov D, Fischer MD. Immune responses to retinal gene therapy using adeno-associated viral vectors: implications for treatment success
and safety. Prog Retin Eye Res 2021;83:100915.
Pagon RA. Retinitis pigmentosa. Surv Ophthalmol 1988;33:137-77.
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;388:661-72.
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;390:849-60.
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;126:1273-85.
Maguire AM, Russell S, Chung DC, et al. Durability of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease: phase 3 results at 3 and 4 years. Ophthalmology 2021;128:1460-8.
Pennesi ME, Weleber RG, Yang P, et al. Results at 5 years after gene therapy for RPE65-deficient retinal dystrophy. Hum Gene Ther 2018;29:1428-37.
Cehajic-Kapetanovic J, Xue K, Martinez-Fernandez de la Camara C, et al. Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. Nat Med 2020;26:354-9.
Lu B, Morgans CW, Girman S, Lund R, Wang S. Retinal morphological and functional changes in an animal model of retinitis pigmentosa. Vis Neurosci 2013;30:77-89.
Ghazi NG, Abboud EB, Nowilaty SR, et al. Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase I trial. Hum Genet 2016;135:327-43.
Zeitz C, Robson AG, Audo I. Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms. Prog Retin Eye Res 2015;45:58-110.
Bijveld MM, Florijn RJ, Bergen AA, et al. Genotype and phenotype of 101 Dutch patients with congenital stationary night blindness. Ophthalmology 2013;120:2072-81.
Waldner DM, Ito K, Chen LL, et al. Transgenic expression of cacna1f rescues vision and retinal morphology in a mouse model of congenital stationary night blindness 2A (CSNB2A). Transl Vis Sci Technol 2020;9:19.
Neuille M, El Shamieh S, Orhan E, et al. Lrit3 deficient mouse (nob6): a novel model of complete congenital stationary night blindness (cCSNB). PLoS One 2014;9:e90342.
Varin J, Bouzidi N, Gauvain G, et al. Substantial restoration of night vision in adult mice with congenital stationary night blindness. Mol Ther Methods Clin Dev 2021;22:15-25.
Pearring JN, Bojang P Jr, Shen Y, et al. A role for nyctalopin, a small leucine-rich repeat protein, in localizing the TRP melastatin 1 channel to retinal depolarizing bipolar cell dendrites. J Neurosci 2011;31:10060-6.
Scalabrino ML, Boye SL, Fransen KM, et al. Intravitreal delivery of a novel AAV vector targets ON bipolar cells and restores visual function in a mouse model of complete congenital stationary night blindness. Hum Mol Genet 2015;24:6229-39.
Johnson S, Michaelides M, Aligianis IA, et al. Achromatopsia caused by novel mutations in both CNGA3 and CNGB3. J Med Genet 2004;41:e20.
Ofri R, Averbukh E, Ezra-Elia R, et al. Six years and counting: restoration of photopic retinal function and visual behavior following gene augmentation therapy in a sheep model of CNGA3 achromatopsia. Hum Gene Ther 2018;29:1376-86.
Fischer MD, Michalakis S, Wilhelm B, et al. Safety and vision outcomes of subretinal gene therapy targeting cone photoreceptors in achromatopsia: a nonrandomized controlled trial. JAMA Ophthalmol 2020;138:643-51.
Reichel FF, Michalakis S, Wilhelm B, et al. Three-year results of phase I retinal gene therapy trial for CNGA3-mutated achromatopsia: results of a non-randomised controlled trial. Br J Ophthalmol 2021:bjophthalmol-2021-319067.
Pavlou M, Schon C, Occelli LM, et al. Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders. EMBO Mol Med 2021;13:e13392.
Ye GJ, Budzynski E, Sonnentag P, et al. Cone-specific promoters for gene therapy of achromatopsia and other retinal diseases. Hum Gene Ther 2016;27:72-82.
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;374:1597-605.
Ripamonti C, Henning GB, Robbie SJ, et al. Spectral sensitivity measurements reveal partial success in restoring missing rod function with gene therapy. J Vis 2015;15:20.
Sarkar H, Moosajee M. Retinol dehydrogenase 12 (RDH12): role in vision, retinal disease and future perspectives. Exp Eye Res 2019;188:107793.
Feathers KL, Jia L, Perera ND, et al. Development of a gene therapy vector for RDH12-associated retinal dystrophy. Hum Gene Ther 2019;30:1325-35.
Jacobson SG, Cideciyan AV, Sumaroka A, et al. Remodeling of the human retina in choroideremia: rab escort protein 1 (REP-1) mutations. Invest Ophthalmol Vis Sci 2006;47:4113-20.
Dimopoulos IS, Hoang SC, Radziwon A, et al. Two-year results after AAV2-mediated gene therapy for choroideremia: the Alberta experience. Am J Ophthalmol 2018;193:130-42.
Fischer MD, Ochakovski GA, Beier B, et al. Efficacy and safety of retinal gene therapy using adeno-associated virus vector for patients with choroideremia: a randomized clinical trial. JAMA Ophthalmol 2019;137:1247-54.
Lam BL, Davis JL, Gregori NZ, et al. Choroideremia gene therapy phase 2 clinical trial: 24-month results. Am J Ophthalmol 2019;197:65-73.
Fischer MD, Ochakovski GA, Beier B, et al. Changes in retinal sensitivity after gene therapy in choroideremia. Retina 2020;40:160-8.
MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 2014;383:1129-37.
Xue K, Jolly JK, Barnard AR, et al. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med 2018;24:1507-12.
Maguire AM, Bennett J, Aleman EM, Leroy BP, Aleman TS. Clinical perspective: treating RPE65-associated retinal dystrophy. Mol Ther 2021;29:442-63.
Prado DA, Acosta-Acero M, Maldonado RS. Gene therapy beyond luxturna: a new horizon of the treatment for inherited retinal disease. Curr Opin Ophthalmol 2020;31:147-54.
Wang D, Wang K, Cai Y. An overview of development in gene therapeutics in China. Gene Ther 2020;27:338-48.
Wang L, Zhang J, Chen N, et al. Application of whole exome and targeted panel sequencing in the clinical molecular diagnosis of 319 Chinese families with inherited retinal dystrophy and comparison study. Genes (Basel) 2018;9:360.
Gao FJ, Li JK, Chen H, et al. Genetic and clinical findings in a large cohort of Chinese patients with suspected retinitis pigmentosa. Ophthalmology 2019;126:1549-56.
Xu Y, Guan L, Shen T, et al. Mutations of 60 known causative genes in 157 families with retinitis pigmentosa based on exome sequencing. Hum Genet 2014;133:1255-71.
Sun Y, Li W, Li JK, et al. Genetic and clinical findings of panel-based targeted exome sequencing in a northeast Chinese cohort with retinitis pigmentosa. Mol Genet Genomic Med 2020;8:e1184.
Dan H, Song X, Li J, Xing Y, Li T. Mutation screening of the LRIT3, CABP4, and GPR179 genes in Chinese patients with Schubert-Bornschein congenital stationary night blindness. Ophthalmic Genet 2017;38:206-10.
Xiao X, Jia X, Guo X, Li S, Yang Z, Zhang Q. CSNB1 in Chinese families associated with novel mutations in NYX. J Hum Genet 2006;51:634-40.
Xu K, Xie Y, Sun T, Zhang X, Chen C, Li Y. Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy. Br J Ophthalmol 2020;104:932-7.
Han X, Wu S, Li H, et al. Clinical characteristics and molecular genetic analysis of a cohort of Chinese patients with choroideremia. Retina 2020;40:2240-53.
Li S, Huang L, Xiao X, Jia X, Guo X, Zhang Q. Identification of CNGA3 mutations in 46 families: common cause of achromatopsia and cone-rod dystrophies in Chinese patients. JAMA Ophthalmol 2014;132:1076-83.
Zuzic M, Rojo Arias JE, Wohl SG, Busskamp V. Retinal miRNA functions in health and disease. Genes (Basel) 2019;10:377.
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