The research status and progress of gene therapy for X-linked juvenile retinoschisis_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Tianlu ¹ ,  Shen Yin ^1,2

1. Eye Center, Renmin Hospital of Wuhan University, Wuhan 430060, China;
2. Medical Research Institute, Wuhan University, Wuhan 430071, China;

Corresponding author：

Shen Yin, Email: yinshen@whu.edu.cn

Keywords：

Retinoschisis; Gene therapy; Review

DOI：

10.3760/cma.j.cn511434-20210816-00439

Video：

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X-linked juvenile retinoschisis (XLRS) is a rare X-linked inherited retinal disorder, mainly affects bilateral retina. Patients often present with visual deterioration accompanied by a spoke-wheel pattern in the macula due to splitting of inner retinal layers and a disproportionate decline in the b-wave relative to a-wave of electroretinogram. The current therapy is mainly directed toward treatment of complications with no effective clinical management yet. In recent years, with the deepening understanding of XLRS, adeno-associated virus(AAV)-mediated gene therapy has become a potential new approach for the treatment. Two clinical trials on XLRS gene therapy are currently underway. These two clinical trials assess the ocular safety and tolerability of recombinant AAV-RS1 vector and explore its safe dose in XLRS patients. However, the recovery of retinal structure and function in XLRS patients is unsatisfactory. Following the in-depth research and progress of clinical trials, it is expected that more accurate and effective treatments for XLRS patients will be provided in the future.

Citation： Zhang Tianlu, Shen Yin. The research status and progress of gene therapy for X-linked juvenile retinoschisis. Chinese Journal of Ocular Fundus Diseases, 2021, 37(11): 891-895. doi: 10.3760/cma.j.cn511434-20210816-00439 Copy

1.	George ND, Yates JR, Moore AT. X linked retinoschisis[J]. Br J Ophthalmol, 1995, 79(7): 697-702. DOI: 10.1136/bjo.79.7.697.
2.	George ND, Yates JR, Moore AT. Clinical features in affected males with X-linked retinoschisis[J]. Arch Ophthalmol, 1996, 114(3): 274-280. DOI: 10.1001/archopht.1996.01100130270007.
3.	Molday RS, Kellner U, Weber BH. X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms[J]. Prog Retin Eye Res, 2012, 31(3): 195-212. DOI: 10.1016/j.preteyeres.2011.12.002.
4.	Sikkink SK, Biswas S, Parry NR, et al. X-linked retinoschisis: an update[J]. J Med Genet, 2007, 44(4): 225-232. DOI: 10.1136/jmg.2006.047340.
5.	Tsang SH, Sharma T. X-linked juvenile retinoschisis[J]. Adv Exp Med Biol, 2018, 1085: 43-48. DOI: 10.1007/978-3-319-95046-4_10.
6.	Molday LL, Hicks D, Sauer CG, et al. Expression of X-linked retinoschisis protein RS1 in photoreceptor and bipolar cells[J]. Invest Ophthalmol Vis Sci, 2001, 42(3): 816-825.
7.	Tantri A, Vrabec TR, Cu-Unjieng A, et al. X-linked retinoschisis: a clinical and molecular genetic review[J]. Surv Ophthalmol, 2004, 49(2): 214-230. DOI: 10.1016/j.survophthal.2003.12.007.
8.	Wang T, Zhou A, Waters CT, et al. Molecular pathology of X linked retinoschisis: mutations interfere with retinoschisin secretion and oligomerisation[J]. Br J Ophthalmol, 2006, 90(1): 81-86. DOI: 10.1136/bjo.2005.078048.
9.	毛子清, 游志鹏. 先天性视网膜劈裂的研究进展[J]. 中国实用眼科杂志, 2016, 34(6): 526-530. DOI: 10.3760/cma.j.issn.1006-4443.2016.06.003.Mao ZQ, You ZP. Research progress of X-linked retinoschisis[J]. Chin J Pract Ophthalmo, 2016, 34(6): 526-530. DOI: 10.3760/cma.j.issn.1006-4443.2016.06.003.
10.	Chen C, Xie Y, Sun T, et al. Clinical findings and RS1 genotype in 90 Chinese families with X-linked retinoschisis[J]. Mol Vis, 2020, 26: 291-298.
11.	沈科炯, 沈吟. 遗传性视网膜疾病腺相关病毒载体基因治疗新进展[J]. 中华眼底病杂志, 2020, 36(3): 242-248. DOI: 10.3760/cma.j.cn511434-20190705-00214.Shen KJ, Shen Y. New advances in gene therapy with adenoviral vectors for inherited retinal diseases[J]. Chin J Ocul Fundus Dis, 2020, 36(3): 242-248. DOI: 10.3760/cma.j.cn511434-20190705-00214.
12.	Rodrigues GA, Shalaev E, Karami TK, et al. Pharmaceutical development of AAV-based gene therapy products for the eye[J]. Pharm Res, 2018, 36(2): 29. DOI: 10.1007/s11095-018-2554-7.
13.	蔡丹瑞, 沈吟. 腺相关病毒在视觉系统神经示踪及眼科治疗中的应用进展[J]. 医学综述, 2020, 26(22): 4440-4444. DOI: 10.3969/j.issn.1006-2084.2020.22.014.Cai DR, Shen Y. Application progress of adeno-associated virus in nerve tracing of visual dystem and ophthalmic treatment[J]. Medical Recapitulate, 2020, 26(22): 4440-4444. DOI: 10.3969/j.issn.1006-2084.2020.22.014.
14.	Moore NA, Morral N, Ciulla TA, et al. Gene therapy for inherited retinal and optic nerve degenerations[J]. Expert Opin Biol Ther, 2018, 18(1): 37-49. DOI: 10.1080/14712598.2018.1389886.
15.	Weber BH, Schrewe H, Molday LL, et al. Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure[J]. Proc Natl Acad Sci USA, 2002, 99(9): 6222-6227. DOI: 10.1073/pnas.092528599.
16.	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[J]. Invest Ophthalmol Vis Sci, 2004, 45(9): 3279-3285. DOI: 10.1167/iovs.04-0576.
17.	Jablonski MM, Dalke C, Wang X, et al. An ENU-induced mutation in Rs1h causes disruption of retinal structure and function[J]. Mol Vis, 2005, 11: 569-581.
18.	Bush RA, Wei LL, Sieving PA. Convergence of human genetics and animal studies: gene therapy for X-linked retinoschisis[J/OL]. Cold Spring Harb Perspect Med, 2015, 5(8): a017368[2015-07-22]. https://pubmed.ncbi.nlm.nih.gov/26101206/. DOI: 10.1101/cshperspect.a017368.
19.	Marangoni D, Wu Z, Wiley HE, et al. Preclinical safety evaluation of a recombinant AAV8 vector for X-linked retinoschisis after intravitreal administration in rabbits[J]. Hum Gene Ther Clin Dev, 2014, 25(4): 202-211. DOI: 10.1089/humc.2014.067.
20.	Marangoni D, Bush RA, Zeng Y, et al. Ocular and systemic safety of a recombinant AAV8 vector for X-linked retinoschisis gene therapy: GLP studies in rabbits and Rs1-KO mice[J/OL]. Mol Ther Methods Clin Dev, 2016, 5: 16011[2016-03-16]. https://pubmed.ncbi.nlm.nih.gov/27626041/. DOI: 10.1038/mtm.2016.11.
21.	Ye GJ, Budzynski E, Sonnentag P, et al. Safety and biodistribution evaluation in cynomolgus macaques of rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus vector expressing retinoschisin[J]. Hum Gene Ther Clin Dev, 2015, 26(3): 165-176. DOI: 10.1089/humc.2015.076.
22.	Ye GJ, Conlon T, Erger K, et al. Safety and biodistribution evaluation of rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus vector expressing retinoschisin, in RS1-deficient mice[J]. Hum Gene Ther Clin Dev, 2015, 26(3): 177-184. DOI: 10.1089/humc.2015.077.
23.	Min SH, Molday LL, Seeliger MW, et al. Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis[J]. Mol Ther, 2005, 12(4): 644-651. DOI: 10.1016/j.ymthe.2005.06.002.
24.	Kjellstrom S, Bush RA, Zeng Y, et al. Retinoschisin gene therapy and natural history in the Rs1h-KO mouse: long-term rescue from retinal degeneration[J]. Invest Ophthalmol Vis Sci, 2007, 48(8): 3837-3845. DOI: 10.1167/iovs.07-0203.
25.	Takada Y, Vijayasarathy C, Zeng Y, et al. Synaptic pathology in retinoschisis knockout (Rs1-/y) mouse retina and modification by rAAV-Rs1 gene delivery[J]. Invest Ophthalmol Vis Sci, 2008, 49(8): 3677-3686. DOI: 10.1167/iovs.07-1071.
26.	Park TK, Wu Z, Kjellstrom S, et al. Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse[J]. Gene Ther, 2009, 16(7): 916-926. DOI: 10.1038/gt.2009.61.
27.	Janssen A, Min SH, Molday LL, et al. Effect of late-stage therapy on disease progression in AAV-mediated rescue of photoreceptor cells in the retinoschisin-deficient mouse[J]. Mol Ther, 2008, 16(6): 1010-1017. DOI: 10.1038/mt.2008.57.
28.	Byrne LC, Oztürk BE, Lee T, et al. Retinoschisin gene therapy in photoreceptors, Müller glia or all retinal cells in the Rs1h-/- mouse[J]. Gene Ther, 2014, 21(6): 585-592. DOI: 10.1038/gt.2014.31.
29.	Ou J, Vijayasarathy C, Ziccardi L, et al. Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer[J]. J Clin Invest, 2015, 125(7): 2891-2903. DOI: 10.1172/JCI81380.
30.	Zeng Y, Petralia RS, Vijayasarathy C, et al. Retinal structure and gene therapy outcome in retinoschisin-deficient mice assessed by spectral-domain optical coherence tomography[J]. Invest Ophthalmol Vis Sci, 2016, 57(9): OCT277-287. DOI: 10.1167/iovs.15-18920.
31.	Vijayasarathy C, Zeng Y, Brooks MJ, et al. Genetic rescue of X-linked retinoschisis mouse (Rs1(-/y)) retina induces quiescence of the retinal microglial inflammatory state following AAV8-RS1 gene transfer and identifies gene networks underlying retinal recovery[J]. Hum Gene Ther, 2020, 32(13-14): 667-681. DOI: 10.1089/hum.2020.213.
32.	Cukras C, Wiley HE, Jeffrey BG, et al. Retinal AAV8-RS1 gene therapy for X-linked retinoschisis: initial findings from a phase Ⅰ/Ⅱa trial by intravitreal delivery[J]. Mol Ther, 2018, 26(9): 2282-2294. DOI: 10.1016/j.ymthe.2018.05.025.
33.	Vijayasarathy C, Sardar Pasha SPB, Sieving PA. Of men and mice: human X-linked retinoschisis and fidelity in mouse modeling[J/OL]. Prog Retin Eye Res, 2021 2021: 100999[2021-08-11]. https://pubmed.ncbi.nlm.nih.gov/34390869/. DOI: 10.1016/j.preteyeres.2021.100999.
34.	Ayton LN, Barnes N, Dagnelie G, et al. An update on retinal prostheses[J]. Clin Neurophysiol, 2020, 131(6): 1383-1398. DOI: 10.1016/j.clinph.2019.11.029.
35.	Garanto A. RNA-based therapeutic strategies for inherited retinal dystrophies[J]. Adv Exp Med Biol, 2019, 1185: 71-77. DOI: 10.1007/978-3-030-27378-1_12.
36.	Ziccardi L, Cordeddu V, Gaddini L, et al. Gene therapy in retinal dystrophies[J]. Int J Mol Sci, 2019, 20(22): 5722. DOI: 10.3390/ijms20225722.
37.	Michalakis S, Gerhardt M, Rudolph G, et al. Gene therapy for inherited retinal disorders: update on clinical trials[J]. Klin Monbl Augenheilkd, 2021, 238(3): 272-281. DOI: 10.1055/a-1384-0818.
38.	Vázquez-Domínguez I, Garanto A, Collin RWJ. Molecular therapies for inherited retinal diseases-current standing, opportunities and challenges[J]. Genes (Basel), 2019, 10(9): 654. DOI: 10.3390/genes10090654.
39.	Benati D, Patrizi C, Recchia A. Gene editing prospects for treating inherited retinal diseases[J]. J Med Genet, 2020, 57(7): 437-444. DOI: 10.1136/jmedgenet-2019-106473.
40.	Afanasyeva TAV, Corral-Serrano JC, Garanto A, et al. A look into retinal organoids: methods, analytical techniques, and applications[J]. Cell Mol Life Sci, 2021, 78(19-20): 6505-6532. DOI: 10.1007/s00018-021-03917-4.
41.	Artero Castro A, Rodríguez Jimenez FJ, Jendelova P, et al. Deciphering retinal diseases through the generation of three dimensional stem cell-derived organoids: concise review[J]. Stem Cells, 2019, 37(12): 1496-1504. DOI: 10.1002/stem.3089.
42.	Simunovic MP, Shen W, Lin JY, et al. Optogenetic approaches to vision restoration[J]. Exp Eye Res, 2019, 178: 15-26. DOI: 10.1016/j.exer.2018.09.003.
43.	Ghezzi D. Translation of a photovoltaic retinal prosthesis[J]. Nat Biomed Eng, 2020, 4(2): 137-138. DOI: 10.1038/s41551-020-0520-2.

1. George ND, Yates JR, Moore AT. X linked retinoschisis[J]. Br J Ophthalmol, 1995, 79(7): 697-702. DOI: 10.1136/bjo.79.7.697.
2. George ND, Yates JR, Moore AT. Clinical features in affected males with X-linked retinoschisis[J]. Arch Ophthalmol, 1996, 114(3): 274-280. DOI: 10.1001/archopht.1996.01100130270007.
3. Molday RS, Kellner U, Weber BH. X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms[J]. Prog Retin Eye Res, 2012, 31(3): 195-212. DOI: 10.1016/j.preteyeres.2011.12.002.
4. Sikkink SK, Biswas S, Parry NR, et al. X-linked retinoschisis: an update[J]. J Med Genet, 2007, 44(4): 225-232. DOI: 10.1136/jmg.2006.047340.
5. Tsang SH, Sharma T. X-linked juvenile retinoschisis[J]. Adv Exp Med Biol, 2018, 1085: 43-48. DOI: 10.1007/978-3-319-95046-4_10.
6. Molday LL, Hicks D, Sauer CG, et al. Expression of X-linked retinoschisis protein RS1 in photoreceptor and bipolar cells[J]. Invest Ophthalmol Vis Sci, 2001, 42(3): 816-825.
7. Tantri A, Vrabec TR, Cu-Unjieng A, et al. X-linked retinoschisis: a clinical and molecular genetic review[J]. Surv Ophthalmol, 2004, 49(2): 214-230. DOI: 10.1016/j.survophthal.2003.12.007.
8. Wang T, Zhou A, Waters CT, et al. Molecular pathology of X linked retinoschisis: mutations interfere with retinoschisin secretion and oligomerisation[J]. Br J Ophthalmol, 2006, 90(1): 81-86. DOI: 10.1136/bjo.2005.078048.
9. 毛子清, 游志鹏. 先天性视网膜劈裂的研究进展[J]. 中国实用眼科杂志, 2016, 34(6): 526-530. DOI: 10.3760/cma.j.issn.1006-4443.2016.06.003.Mao ZQ, You ZP. Research progress of X-linked retinoschisis[J]. Chin J Pract Ophthalmo, 2016, 34(6): 526-530. DOI: 10.3760/cma.j.issn.1006-4443.2016.06.003.
10. Chen C, Xie Y, Sun T, et al. Clinical findings and RS1 genotype in 90 Chinese families with X-linked retinoschisis[J]. Mol Vis, 2020, 26: 291-298.
11. 沈科炯, 沈吟. 遗传性视网膜疾病腺相关病毒载体基因治疗新进展[J]. 中华眼底病杂志, 2020, 36(3): 242-248. DOI: 10.3760/cma.j.cn511434-20190705-00214.Shen KJ, Shen Y. New advances in gene therapy with adenoviral vectors for inherited retinal diseases[J]. Chin J Ocul Fundus Dis, 2020, 36(3): 242-248. DOI: 10.3760/cma.j.cn511434-20190705-00214.
12. Rodrigues GA, Shalaev E, Karami TK, et al. Pharmaceutical development of AAV-based gene therapy products for the eye[J]. Pharm Res, 2018, 36(2): 29. DOI: 10.1007/s11095-018-2554-7.
13. 蔡丹瑞, 沈吟. 腺相关病毒在视觉系统神经示踪及眼科治疗中的应用进展[J]. 医学综述, 2020, 26(22): 4440-4444. DOI: 10.3969/j.issn.1006-2084.2020.22.014.Cai DR, Shen Y. Application progress of adeno-associated virus in nerve tracing of visual dystem and ophthalmic treatment[J]. Medical Recapitulate, 2020, 26(22): 4440-4444. DOI: 10.3969/j.issn.1006-2084.2020.22.014.
14. Moore NA, Morral N, Ciulla TA, et al. Gene therapy for inherited retinal and optic nerve degenerations[J]. Expert Opin Biol Ther, 2018, 18(1): 37-49. DOI: 10.1080/14712598.2018.1389886.
15. Weber BH, Schrewe H, Molday LL, et al. Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure[J]. Proc Natl Acad Sci USA, 2002, 99(9): 6222-6227. DOI: 10.1073/pnas.092528599.
16. 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[J]. Invest Ophthalmol Vis Sci, 2004, 45(9): 3279-3285. DOI: 10.1167/iovs.04-0576.
17. Jablonski MM, Dalke C, Wang X, et al. An ENU-induced mutation in Rs1h causes disruption of retinal structure and function[J]. Mol Vis, 2005, 11: 569-581.
18. Bush RA, Wei LL, Sieving PA. Convergence of human genetics and animal studies: gene therapy for X-linked retinoschisis[J/OL]. Cold Spring Harb Perspect Med, 2015, 5(8): a017368[2015-07-22]. https://pubmed.ncbi.nlm.nih.gov/26101206/. DOI: 10.1101/cshperspect.a017368.
19. Marangoni D, Wu Z, Wiley HE, et al. Preclinical safety evaluation of a recombinant AAV8 vector for X-linked retinoschisis after intravitreal administration in rabbits[J]. Hum Gene Ther Clin Dev, 2014, 25(4): 202-211. DOI: 10.1089/humc.2014.067.
20. Marangoni D, Bush RA, Zeng Y, et al. Ocular and systemic safety of a recombinant AAV8 vector for X-linked retinoschisis gene therapy: GLP studies in rabbits and Rs1-KO mice[J/OL]. Mol Ther Methods Clin Dev, 2016, 5: 16011[2016-03-16]. https://pubmed.ncbi.nlm.nih.gov/27626041/. DOI: 10.1038/mtm.2016.11.
21. Ye GJ, Budzynski E, Sonnentag P, et al. Safety and biodistribution evaluation in cynomolgus macaques of rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus vector expressing retinoschisin[J]. Hum Gene Ther Clin Dev, 2015, 26(3): 165-176. DOI: 10.1089/humc.2015.076.
22. Ye GJ, Conlon T, Erger K, et al. Safety and biodistribution evaluation of rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus vector expressing retinoschisin, in RS1-deficient mice[J]. Hum Gene Ther Clin Dev, 2015, 26(3): 177-184. DOI: 10.1089/humc.2015.077.
23. Min SH, Molday LL, Seeliger MW, et al. Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis[J]. Mol Ther, 2005, 12(4): 644-651. DOI: 10.1016/j.ymthe.2005.06.002.
24. Kjellstrom S, Bush RA, Zeng Y, et al. Retinoschisin gene therapy and natural history in the Rs1h-KO mouse: long-term rescue from retinal degeneration[J]. Invest Ophthalmol Vis Sci, 2007, 48(8): 3837-3845. DOI: 10.1167/iovs.07-0203.
25. Takada Y, Vijayasarathy C, Zeng Y, et al. Synaptic pathology in retinoschisis knockout (Rs1-/y) mouse retina and modification by rAAV-Rs1 gene delivery[J]. Invest Ophthalmol Vis Sci, 2008, 49(8): 3677-3686. DOI: 10.1167/iovs.07-1071.
26. Park TK, Wu Z, Kjellstrom S, et al. Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse[J]. Gene Ther, 2009, 16(7): 916-926. DOI: 10.1038/gt.2009.61.
27. Janssen A, Min SH, Molday LL, et al. Effect of late-stage therapy on disease progression in AAV-mediated rescue of photoreceptor cells in the retinoschisin-deficient mouse[J]. Mol Ther, 2008, 16(6): 1010-1017. DOI: 10.1038/mt.2008.57.
28. Byrne LC, Oztürk BE, Lee T, et al. Retinoschisin gene therapy in photoreceptors, Müller glia or all retinal cells in the Rs1h-/- mouse[J]. Gene Ther, 2014, 21(6): 585-592. DOI: 10.1038/gt.2014.31.
29. Ou J, Vijayasarathy C, Ziccardi L, et al. Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer[J]. J Clin Invest, 2015, 125(7): 2891-2903. DOI: 10.1172/JCI81380.
30. Zeng Y, Petralia RS, Vijayasarathy C, et al. Retinal structure and gene therapy outcome in retinoschisin-deficient mice assessed by spectral-domain optical coherence tomography[J]. Invest Ophthalmol Vis Sci, 2016, 57(9): OCT277-287. DOI: 10.1167/iovs.15-18920.
31. Vijayasarathy C, Zeng Y, Brooks MJ, et al. Genetic rescue of X-linked retinoschisis mouse (Rs1(-/y)) retina induces quiescence of the retinal microglial inflammatory state following AAV8-RS1 gene transfer and identifies gene networks underlying retinal recovery[J]. Hum Gene Ther, 2020, 32(13-14): 667-681. DOI: 10.1089/hum.2020.213.
32. Cukras C, Wiley HE, Jeffrey BG, et al. Retinal AAV8-RS1 gene therapy for X-linked retinoschisis: initial findings from a phase Ⅰ/Ⅱa trial by intravitreal delivery[J]. Mol Ther, 2018, 26(9): 2282-2294. DOI: 10.1016/j.ymthe.2018.05.025.
33. Vijayasarathy C, Sardar Pasha SPB, Sieving PA. Of men and mice: human X-linked retinoschisis and fidelity in mouse modeling[J/OL]. Prog Retin Eye Res, 2021 2021: 100999[2021-08-11]. https://pubmed.ncbi.nlm.nih.gov/34390869/. DOI: 10.1016/j.preteyeres.2021.100999.
34. Ayton LN, Barnes N, Dagnelie G, et al. An update on retinal prostheses[J]. Clin Neurophysiol, 2020, 131(6): 1383-1398. DOI: 10.1016/j.clinph.2019.11.029.
35. Garanto A. RNA-based therapeutic strategies for inherited retinal dystrophies[J]. Adv Exp Med Biol, 2019, 1185: 71-77. DOI: 10.1007/978-3-030-27378-1_12.
36. Ziccardi L, Cordeddu V, Gaddini L, et al. Gene therapy in retinal dystrophies[J]. Int J Mol Sci, 2019, 20(22): 5722. DOI: 10.3390/ijms20225722.
37. Michalakis S, Gerhardt M, Rudolph G, et al. Gene therapy for inherited retinal disorders: update on clinical trials[J]. Klin Monbl Augenheilkd, 2021, 238(3): 272-281. DOI: 10.1055/a-1384-0818.
38. Vázquez-Domínguez I, Garanto A, Collin RWJ. Molecular therapies for inherited retinal diseases-current standing, opportunities and challenges[J]. Genes (Basel), 2019, 10(9): 654. DOI: 10.3390/genes10090654.
39. Benati D, Patrizi C, Recchia A. Gene editing prospects for treating inherited retinal diseases[J]. J Med Genet, 2020, 57(7): 437-444. DOI: 10.1136/jmedgenet-2019-106473.
40. Afanasyeva TAV, Corral-Serrano JC, Garanto A, et al. A look into retinal organoids: methods, analytical techniques, and applications[J]. Cell Mol Life Sci, 2021, 78(19-20): 6505-6532. DOI: 10.1007/s00018-021-03917-4.
41. Artero Castro A, Rodríguez Jimenez FJ, Jendelova P, et al. Deciphering retinal diseases through the generation of three dimensional stem cell-derived organoids: concise review[J]. Stem Cells, 2019, 37(12): 1496-1504. DOI: 10.1002/stem.3089.
42. Simunovic MP, Shen W, Lin JY, et al. Optogenetic approaches to vision restoration[J]. Exp Eye Res, 2019, 178: 15-26. DOI: 10.1016/j.exer.2018.09.003.
43. Ghezzi D. Translation of a photovoltaic retinal prosthesis[J]. Nat Biomed Eng, 2020, 4(2): 137-138. DOI: 10.1038/s41551-020-0520-2.

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