Progress in diagnosis and treatment of retinitis pigmentosa_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Hongli ,  Wu Jihong

Department of Ophthalmology, Affiliated Ophthalmology and Otolaryngology Hospital of Fudan University, Shanghai 200031, China;

Corresponding author：

Wu Jihong, Email: jihongwu@fudan.edu.cn

Keywords：

Retinitis pigmentosa; Gene therapy; Review

DOI：

10.3760/cma.j.cn511434-20210319-00147

Video：

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Retinitis pigmentosa is a hereditary disease which is characterized by damage in retinal photoreceptor cells and retinal pigment epithelium. Its main clinical features include low vision with night blindness, progressive visual field defects, and abnormal electroretinograms. The development of gene sequencing, the diagnosis and treatment methods of retinitis pigmentosa update year by year, including gene therapy, stem cell therapy, optogenetic therapy, etc. However, there is still a big gap in these treatments from laboratory technology into effective clinical treatment drugs. Some problems which include immune response, potential mutagenesis and tumorigenesis of the inserted region, genetic toxicity, quality and stability of gene technology and stem cell technology, mass production and promotion of clinical grade drugs, and optimization of the effectiveness of drugs and surgery, etc, remain to be solved by researchers.

Citation： Liu Hongli, Wu Jihong. Progress in diagnosis and treatment of retinitis pigmentosa. Chinese Journal of Ocular Fundus Diseases, 2021, 37(11): 896-900. doi: 10.3760/cma.j.cn511434-20210319-00147 Copy

1.	Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa[J]. Lancet, 2006, 368(9549): 1795-1809. DOI: 10.1016/s0140-6736(06)69740-7.
2.	Petit L, Khanna H, Punzo C. Advances in gene therapy for diseases of the eye[J]. Hum Gene Ther, 2016, 27(8): 563-579. DOI: 10.1089/hum.2016.040.
3.	Roska B, Busskamp V, Sahel JA, et al. Retinitis pigmentosa: eye sight restoration by optogenetic therapy[J]. Biol Aujourdhui, 2013, 207(2): 109-121. DOI: 10.1051/jbio/2013011.
4.	Maeda A, Mandai M, Takahashi M. Gene and induced pluripotent stem cell therapy for retinal diseases[J]. Annu Rev Genomics Hum Genet, 2019, 20: 201-216. DOI: 10.1146/annurev-genom-083118-015043.
5.	Koyanagi Y, Akiyama M, Nishiguchi KM, et al. Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients[J]. J Med Genet, 2019, 56(10): 662-670. DOI: 10.1136/jmedgenet-2018-105691.
6.	Verbakel SK, van Huet RAC, Boon CJF, et al. Non-syndromic retinitis pigmentosa[J]. Prog Retin Eye Res, 2018, 66: 157-186. DOI: 10.1016/j.preteyeres.2018.03.005.
7.	Salmaninejad A, Motaee J, Farjami M, et al. Next-generation sequencing and its application in diagnosis of retinitis pigmentosa[J]. Ophthalmic Genet, 2019, 40(5): 393-402. DOI: 10.1080/13816810.2019.1675178.
8.	Tuson M, Marfany G, Gonzàlez-Duarte R. Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26)[J]. Am J Hum Genet, 2004, 74(1): 128-138. DOI: 10.1086/381055.
9.	Papaioannou M, Chakarova CF, Prescott DC, et al. A new locus (RP31) for autosomal dominant retinitis pigmentosa maps to chromosome 9p[J]. Hum Genet, 2005, 118(3-4): 501-503. DOI: 10.1007/s00439-005-0063-3.
10.	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.
11.	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[J]. Mol Ther, 2005, 12(6): 1072-1082. DOI: 10.1016/j.ymthe.2005.08.008.
12.	Bennicelli J, Wright JF, Komaromy A, et al. Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transfer[J]. Mol Ther, 2008, 16(3): 458-465. DOI: 10.1038/sj.mt.6300389.
13.	Cuevas E, Parmar P, Sowden JC. Restoring vision using stem cells and transplantation[J]. Adv Exp Med Biol, 2019, 1185: 563-567. DOI: 10.1007/978-3-030-27378-1_92.
14.	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[J]. Lancet, 2016, 388(10045): 661-672. DOI: 10.1016/s0140-6736(16)30371-3.
15.	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[J]. Mol Ther, 2018, 26(1): 256-268. DOI: 10.1016/j.ymthe.2017.09.014.
16.	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[J]. Arch Ophthalmol, 2012, 130(1): 9-24. DOI: 10.1001/archophthalmol.2011.298.
17.	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[J]. Nat Med, 2020, 26(3): 354-359. DOI: 10.1038/s41591-020-0763-1.
18.	Lane A, Jovanovic K, Shortall C, et al. Modeling and rescue of RP2 retinitis pigmentosa using iPSC-derived retinal organoids[J]. Stem Cell Reports, 2020, 15(1): 67-79. DOI: 10.1016/j.stemcr.2020.05.007.
19.	Wert KJ, Davis RJ, Sancho-Pelluz J, et al. Gene therapy provides long-term visual function in a pre-clinical model of retinitis pigmentosa[J]. Hum Mol Genet, 2013, 22(3): 558-567. DOI: 10.1093/hmg/dds466.
20.	Wert KJ, Sancho-Pelluz J, Tsang SH. Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa[J]. Hum Mol Genet, 2014, 23(2): 514-523. DOI: 10.1093/hmg/ddt452.
21.	Mowat FM, Occelli LM, Bartoe JT, et al. Gene therapy in a large animal model of PDE6A-retinitis pigmentosa[J/OL]. Front Neurosci, 2017, 11: 342[2017-06-20]. https://pubmed.ncbi.nlm.nih.gov/28676737/. DOI: 10.3389/fnins.2017.00342.
22.	Petersen-Jones SM, Occelli LM, Biel M, et al. Advancing gene therapy for PDE6A retinitis pigmentosa[J]. Adv Exp Med Biol, 2019, 1185: 103-107. DOI: 10.1007/978-3-030-27378-1_17.
23.	Pichard V, Provost N, Mendes-Madeira A, et al. AAV-mediated gene therapy halts retinal degeneration in PDE6β-deficient dogs[J]. Mol Ther, 2016, 24(5): 867-876. DOI: 10.1038/mt.2016.37.
24.	Choi VW, Bigelow CE, Mcgee TL, et al. AAV-mediated RLBP1 gene therapy improves the rate of dark adaptation in Rlbp1 knockout mice[J/OL]. Mol Ther Methods Clin Dev, 2015, 2: 15022[2015-07-08]. https://pubmed.ncbi.nlm.nih.gov/26199951/. DOI: 10.1038/mtm.2015.22.
25.	Bennett J. Gene therapy for retinitis pigmentosa[J]. Curr Opin Mol Ther, 2000, 2(4): 420-425.
26.	Sudharsan R, Beltran WA. Progress in gene therapy for rhodopsin autosomal dominant retinitis pigmentosa[J]. Adv Exp Med Biol, 2019, 1185: 113-118. DOI: 10.1007/978-3-030-27378-1_19.
27.	Toualbi L, Toms M, Moosajee M. USH2A-retinopathy: from genetics to therapeutics[J/OL]. Exp Eye Res, 2020, 201: 108330[2020-10-27]. https://pubmed.ncbi.nlm.nih.gov/33121974/. DOI: 10.1016/j.exer.2020.108330.
28.	Cideciyan AV, Sudharsan R, Dufour VL, et al. Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector[J/OL]. Proc Natl Acad Sci USA, 2018, 115(36): E8547-E8556[2018-08-20].https://pubmed.ncbi.nlm.nih.gov/30127005/. DOI: 10.1073/pnas.1805055115.
29.	Jacobson SG, Cideciyan AV, Roman AJ, et al. Improvement and decline in vision with gene therapy in childhood blindness[J]. N Engl J Med, 2015, 372(20): 1920-1926. DOI: 10.1056/NEJMoa1412965.
30.	Bainbridge JW, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber's congenital amaurosis[J]. N Engl J Med, 2015, 372(20): 1887-1897. DOI: 10.1056/NEJMoa1414221.
31.	Duebel J, Marazova K, Sahel JA. Optogenetics[J]. Curr Opin Ophthalmol, 2015, 26(3): 226-232. DOI: 10.1097/icu.0000000000000140.
32.	Busskamp V, Picaud S, Sahel JA, et al. Optogenetic therapy for retinitis pigmentosa[J]. Gene Ther, 2012, 19(2): 169-175. DOI: 10.1038/gt.2011.155.
33.	Bionic sight, LLC doses first patient in a phase 1/2 clinical trial of a new investigational treatment for blindness caused by retinitis pigmentosa[EB/OL]. (2020-06-16)[2021-03-19].https://www.biospace.com/article/releases/bionic-sight-llc-doses-first-patient-in-a-phase-1-2-clinical-trial-of-a-new-investigational-treatment-for-blindness-caused-by-retinitis-pigmentosa/.
34.	Das T, Del Cerro M, Jalali S, et al. The transplantation of human fetal neuroretinal cells in advanced retinitis pigmentosa patients: results of a long-term safety study[J]. Exp Neurol, 1999, 157(1): 58-68. DOI: 10.1006/exnr.1998.6992.
35.	Maclaren RE, Pearson RA, Macneil A, et al. Retinal repair by transplantation of photoreceptor precursors[J]. Nature, 2006, 444(7116): 203-207. DOI: 10.1038/nature05161.
36.	Pearson RA, Barber AC, Rizzi M, et al. Restoration of vision after transplantation of photoreceptors[J]. Nature, 2012, 485(7396): 99-103. DOI: 10.1038/nature10997.
37.	Kuppermann BD, Boyer DS, Mills B, et al. Safety and activity of a single, intravitreal injection of human retinal progenitor cells (jCell) for treatment of retinitis pigmentosa (RP)[J]. Investig Ophthalmol Vis Sci, 2018, 59(9): 2987.
38.	ReNeuron announces presentation of updated efficacy and safety data from retinitis pigmentosa study at the sixth annual retinal cell and gene therapy innovation summit[EB/OL]. (2019-04-26)[2021-03-19].https://www.prnewswire.com/news-releases/reneuron-announces-presentation-of-updated-efficacy-and-safety-data-from-retinitis-pigmentosa-study-at-the-sixth-annual-retinal-cell-and-gene-therapy-innovation-summit-300838843.html.
39.	Maclaren RE, Pearson RA. Stem cell therapy and the retina[J]. Eye, 2007, 21(10): 1352-1359. DOI: 10.1038/sj.eye.6702842.

1. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa[J]. Lancet, 2006, 368(9549): 1795-1809. DOI: 10.1016/s0140-6736(06)69740-7.
2. Petit L, Khanna H, Punzo C. Advances in gene therapy for diseases of the eye[J]. Hum Gene Ther, 2016, 27(8): 563-579. DOI: 10.1089/hum.2016.040.
3. Roska B, Busskamp V, Sahel JA, et al. Retinitis pigmentosa: eye sight restoration by optogenetic therapy[J]. Biol Aujourdhui, 2013, 207(2): 109-121. DOI: 10.1051/jbio/2013011.
4. Maeda A, Mandai M, Takahashi M. Gene and induced pluripotent stem cell therapy for retinal diseases[J]. Annu Rev Genomics Hum Genet, 2019, 20: 201-216. DOI: 10.1146/annurev-genom-083118-015043.
5. Koyanagi Y, Akiyama M, Nishiguchi KM, et al. Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients[J]. J Med Genet, 2019, 56(10): 662-670. DOI: 10.1136/jmedgenet-2018-105691.
6. Verbakel SK, van Huet RAC, Boon CJF, et al. Non-syndromic retinitis pigmentosa[J]. Prog Retin Eye Res, 2018, 66: 157-186. DOI: 10.1016/j.preteyeres.2018.03.005.
7. Salmaninejad A, Motaee J, Farjami M, et al. Next-generation sequencing and its application in diagnosis of retinitis pigmentosa[J]. Ophthalmic Genet, 2019, 40(5): 393-402. DOI: 10.1080/13816810.2019.1675178.
8. Tuson M, Marfany G, Gonzàlez-Duarte R. Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26)[J]. Am J Hum Genet, 2004, 74(1): 128-138. DOI: 10.1086/381055.
9. Papaioannou M, Chakarova CF, Prescott DC, et al. A new locus (RP31) for autosomal dominant retinitis pigmentosa maps to chromosome 9p[J]. Hum Genet, 2005, 118(3-4): 501-503. DOI: 10.1007/s00439-005-0063-3.
10. 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.
11. 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[J]. Mol Ther, 2005, 12(6): 1072-1082. DOI: 10.1016/j.ymthe.2005.08.008.
12. Bennicelli J, Wright JF, Komaromy A, et al. Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transfer[J]. Mol Ther, 2008, 16(3): 458-465. DOI: 10.1038/sj.mt.6300389.
13. Cuevas E, Parmar P, Sowden JC. Restoring vision using stem cells and transplantation[J]. Adv Exp Med Biol, 2019, 1185: 563-567. DOI: 10.1007/978-3-030-27378-1_92.
14. 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[J]. Lancet, 2016, 388(10045): 661-672. DOI: 10.1016/s0140-6736(16)30371-3.
15. 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[J]. Mol Ther, 2018, 26(1): 256-268. DOI: 10.1016/j.ymthe.2017.09.014.
16. 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[J]. Arch Ophthalmol, 2012, 130(1): 9-24. DOI: 10.1001/archophthalmol.2011.298.
17. 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[J]. Nat Med, 2020, 26(3): 354-359. DOI: 10.1038/s41591-020-0763-1.
18. Lane A, Jovanovic K, Shortall C, et al. Modeling and rescue of RP2 retinitis pigmentosa using iPSC-derived retinal organoids[J]. Stem Cell Reports, 2020, 15(1): 67-79. DOI: 10.1016/j.stemcr.2020.05.007.
19. Wert KJ, Davis RJ, Sancho-Pelluz J, et al. Gene therapy provides long-term visual function in a pre-clinical model of retinitis pigmentosa[J]. Hum Mol Genet, 2013, 22(3): 558-567. DOI: 10.1093/hmg/dds466.
20. Wert KJ, Sancho-Pelluz J, Tsang SH. Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa[J]. Hum Mol Genet, 2014, 23(2): 514-523. DOI: 10.1093/hmg/ddt452.
21. Mowat FM, Occelli LM, Bartoe JT, et al. Gene therapy in a large animal model of PDE6A-retinitis pigmentosa[J/OL]. Front Neurosci, 2017, 11: 342[2017-06-20]. https://pubmed.ncbi.nlm.nih.gov/28676737/. DOI: 10.3389/fnins.2017.00342.
22. Petersen-Jones SM, Occelli LM, Biel M, et al. Advancing gene therapy for PDE6A retinitis pigmentosa[J]. Adv Exp Med Biol, 2019, 1185: 103-107. DOI: 10.1007/978-3-030-27378-1_17.
23. Pichard V, Provost N, Mendes-Madeira A, et al. AAV-mediated gene therapy halts retinal degeneration in PDE6β-deficient dogs[J]. Mol Ther, 2016, 24(5): 867-876. DOI: 10.1038/mt.2016.37.
24. Choi VW, Bigelow CE, Mcgee TL, et al. AAV-mediated RLBP1 gene therapy improves the rate of dark adaptation in Rlbp1 knockout mice[J/OL]. Mol Ther Methods Clin Dev, 2015, 2: 15022[2015-07-08]. https://pubmed.ncbi.nlm.nih.gov/26199951/. DOI: 10.1038/mtm.2015.22.
25. Bennett J. Gene therapy for retinitis pigmentosa[J]. Curr Opin Mol Ther, 2000, 2(4): 420-425.
26. Sudharsan R, Beltran WA. Progress in gene therapy for rhodopsin autosomal dominant retinitis pigmentosa[J]. Adv Exp Med Biol, 2019, 1185: 113-118. DOI: 10.1007/978-3-030-27378-1_19.
27. Toualbi L, Toms M, Moosajee M. USH2A-retinopathy: from genetics to therapeutics[J/OL]. Exp Eye Res, 2020, 201: 108330[2020-10-27]. https://pubmed.ncbi.nlm.nih.gov/33121974/. DOI: 10.1016/j.exer.2020.108330.
28. Cideciyan AV, Sudharsan R, Dufour VL, et al. Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector[J/OL]. Proc Natl Acad Sci USA, 2018, 115(36): E8547-E8556[2018-08-20].https://pubmed.ncbi.nlm.nih.gov/30127005/. DOI: 10.1073/pnas.1805055115.
29. Jacobson SG, Cideciyan AV, Roman AJ, et al. Improvement and decline in vision with gene therapy in childhood blindness[J]. N Engl J Med, 2015, 372(20): 1920-1926. DOI: 10.1056/NEJMoa1412965.
30. Bainbridge JW, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber's congenital amaurosis[J]. N Engl J Med, 2015, 372(20): 1887-1897. DOI: 10.1056/NEJMoa1414221.
31. Duebel J, Marazova K, Sahel JA. Optogenetics[J]. Curr Opin Ophthalmol, 2015, 26(3): 226-232. DOI: 10.1097/icu.0000000000000140.
32. Busskamp V, Picaud S, Sahel JA, et al. Optogenetic therapy for retinitis pigmentosa[J]. Gene Ther, 2012, 19(2): 169-175. DOI: 10.1038/gt.2011.155.
33. Bionic sight, LLC doses first patient in a phase 1/2 clinical trial of a new investigational treatment for blindness caused by retinitis pigmentosa[EB/OL]. (2020-06-16)[2021-03-19].https://www.biospace.com/article/releases/bionic-sight-llc-doses-first-patient-in-a-phase-1-2-clinical-trial-of-a-new-investigational-treatment-for-blindness-caused-by-retinitis-pigmentosa/.
34. Das T, Del Cerro M, Jalali S, et al. The transplantation of human fetal neuroretinal cells in advanced retinitis pigmentosa patients: results of a long-term safety study[J]. Exp Neurol, 1999, 157(1): 58-68. DOI: 10.1006/exnr.1998.6992.
35. Maclaren RE, Pearson RA, Macneil A, et al. Retinal repair by transplantation of photoreceptor precursors[J]. Nature, 2006, 444(7116): 203-207. DOI: 10.1038/nature05161.
36. Pearson RA, Barber AC, Rizzi M, et al. Restoration of vision after transplantation of photoreceptors[J]. Nature, 2012, 485(7396): 99-103. DOI: 10.1038/nature10997.
37. Kuppermann BD, Boyer DS, Mills B, et al. Safety and activity of a single, intravitreal injection of human retinal progenitor cells (jCell) for treatment of retinitis pigmentosa (RP)[J]. Investig Ophthalmol Vis Sci, 2018, 59(9): 2987.
38. ReNeuron announces presentation of updated efficacy and safety data from retinitis pigmentosa study at the sixth annual retinal cell and gene therapy innovation summit[EB/OL]. (2019-04-26)[2021-03-19].https://www.prnewswire.com/news-releases/reneuron-announces-presentation-of-updated-efficacy-and-safety-data-from-retinitis-pigmentosa-study-at-the-sixth-annual-retinal-cell-and-gene-therapy-innovation-summit-300838843.html.
39. Maclaren RE, Pearson RA. Stem cell therapy and the retina[J]. Eye, 2007, 21(10): 1352-1359. DOI: 10.1038/sj.eye.6702842.

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