Expert consensus on the operative safety management and visual function evaluation index setting of gene therapy for inherited retinal diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

 Fundus Disease Group of Chinese Medical Association Ophthalmology Branch ,  Fundus Disease Committee of Chinese Medical Doctor Association Ophthalmology Branch

Corresponding author: Xun Xu, Email: drxuxun@sjtu.edu.cn; Li Xiaoxin, Email: drlixiaoxin@163.com;

Corresponding?author：

Keywords：

Eye diseases, hereditary; Retinal diseases; Gene therapy; Perioperative period; Consensus International Practice Guidelines register: http://www.guidelines-registry.cn/, IPGRP-2022CN348

DOI：

10.3760/cma.j.cn511434-20220808-00442

Video：

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Abstract Full text Figures/Tables Video References Cited by

Inherited retinal diseases (IRDs) are a group of severe retinal degenerative diseases leading to permanent visual impairment. IRDs are the major cause of irreversible blindness in children and working age groups. Gene therapy is a new clinical treatment method and currently the only clear and effective treatment for IRDs, while, there are still risks in clinical research and application. How to standardize perioperative management and reduce the potential risks of treatment is one of the keys to ensure the safety and effectiveness of treatment. However, there is no systematic and standardized guidance on the perioperative management for IRDs gene therapy. Therefore, in order to standardize the perioperative management, the Fundus Disease Group of Ophthalmology Society of Chinese Medical Association and Chinese Medical Doctor Association organized domestic experts to put forward standardized opinions on the perioperative management of IRDs gene therapy in China after repeated discussion and combined with domestic and foreign research experience, so as to provide clinicians with reference and application in clinical research and practice.

Citation： Fundus Disease Group of Chinese Medical Association Ophthalmology Branch, Fundus Disease Committee of Chinese Medical Doctor Association Ophthalmology Branch. Expert consensus on the operative safety management and visual function evaluation index setting of gene therapy for inherited retinal diseases. Chinese Journal of Ocular Fundus Diseases, 2022, 38(8): 636-642. doi: 10.3760/cma.j.cn511434-20220808-00442 Copy

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6.	Hinderer C, Katz N, Buza EL, et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN[J]. Hum Gene Ther, 2018, 29(3): 285-298. DOI: 10.1089/hum.2018.015.
7.	Philippidis A. Fourth boy dies in clinical trial of Astellas' AT132[J]. Hum Gene Ther, 2021, 32(19-20): 1008-1010. DOI: 10.1089/hum.2021.29182.bfs.
8.	Greenberg B, Butler J, Felker GM, et al. Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure[J]. Gene Ther, 2016, 23(3): 313-319. DOI: 10.1038/gt.2015.109.
9.	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.
10.	Boyd RF, Boye SL, Conlon TJ, et al. Reduced retinal transduction and enhanced transgene-directed immunogenicity with intravitreal delivery of rAAV following posterior vitrectomy in dogs[J]. Gene Ther, 2016, 23(6): 548-556. DOI: 10.1038/gt.2016.31.
11.	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[J]. JAMA Ophthalmol, 2019, 137(11): 1247-1254. DOI: 10.1001/jamaophthalmol.2019.3278.
12.	Ye GJ, Budzynski E, Sonnentag P, et al. Safety and biodistribution evaluation in cynomolgus macaques of rAAV2tYF-PR1.7-hCNGB3, a recombinant AAV vector for treatment of achromatopsia[J]. Hum Gene Ther Clin Dev, 2016, 27(1): 37-48. DOI: 10.1089/humc.2015.164.
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15.	Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis[J]. N Engl J Med, 2008, 358(21): 2231-2239. DOI: 10.1056/NEJMoa0802268.
16.	彭曉燕, 張永鵬. 正確合理使用糖皮質激素: 一個眼底病治療中仍需重視的問題[J]. 中華眼底病雜志, 2011, 27(3): 207-209. DOI: 10.3760/cma.j.issn.1005-1015.2011.03.002.Peng XY, Zhang YP. Think twice before you go: some issues of corticosteroid application in the treatment of ocular fundus diseases[J]. Chin J Ocul Fundus Dis, 2011, 27(3): 207-209. DOI: 10.3760/cma.j.issn.1005-1015.2011.03.002.
17.	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[J]. Lancet, 2009, 374(9701): 1597-1605. DOI: 10.1016/S0140-6736(09)61836-5.
18.	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[J]. Ophthalmology, 2019, 126(9): 1273-1285. DOI: 10.1016/j.ophtha.2019.06.017.
19.	Bucher K, Rodríguez-Bocanegra E, Dauletbekov D, et al. Immune responses to retinal gene therapy using adeno-associated viral vectors-implications for treatment success and safety[J/OL]. Prog Retin Eye Res, 2021, 83: 100915[2020-10-15]. https://pubmed.ncbi.nlm.nih.gov/33069860/. DOI: 10.1016/j.preteyeres.2020.100915.
20.	Cideciyan AV, Jacobson SG, Drack AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect[J]. Nat Med, 2019, 25(2): 225-228. DOI: 10.1038/s41591-018-0295-0.
21.	Nussenblatt RB, Palestine AG, Chan CC, et al. Standardization of vitreal inflammatory activity in intermediate and posterior uveitis[J]. Ophthalmology, 1985, 92(4): 467-471. DOI: 10.1016/s0161-6420(85)34001-0.
22.	Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop[J]. Am J Ophthalmol, 2005, 140(3): 509-516. DOI: 10.1016/j.ajo.2005.03.057.
23.	Bouquet C, Vignal Clermont C, Galy A, et al. Immune response and intraocular inflammation in patients with Leber hereditary optic neuropathy treated with intravitreal injection of recombinant adeno-associated virus 2 carrying the ND4 gene: a secondary analysis of a phase 1/2 clinical trial[J]. JAMA Ophthalmol, 2019, 137(4): 399-406. DOI: 10.1001/jamaophthalmol.2018.6902.
24.	楊培增. 關注我國葡萄膜炎的病因和類型的變化[J]. 中華眼科雜志, 2008, 44(10): 865-866. DOI: 10.3321/j.issn:0412-4081.2008.10.001.Yang PZ. Concern on the changes of clinical pattern and etiological factors in uveitis in China[J]. Chin J Ophthalmol, 2008, 44(10): 865-866. DOI: 10.3321/j.issn:0412-4081.2008.10.001.
25.	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.
26.	Gange WS, Sisk RA, Besirli CG, et al. Perifoveal chorioretinal atrophy after subretinal voretigene neparvovec-rzyl for RPE65-mediated Leber congenital amaurosis[J]. Ophthalmol Retina, 2022, 6(1): 58-64. DOI: 10.1016/j.oret.2021.03.016.
27.	中華醫學會眼科學分會眼底病學組, 中華醫學會眼科學分會白內障及屈光手術學組中華醫學會眼科學分會眼外傷學組, 中華醫學會眼科學分會青光眼學組. 中國眼科手術后感染性眼內炎診療專家共識(2022年)[J]. 中華眼科雜志, 2022, 58(7): 487-499. DOI: 10.3760/cma.j.cn112142-20220301-00088.Fundus Diseases Group of Ophthalmology Branch of Chinese Medical Association, Cataract and Refractive Surgery Group of Ophthalmology Branch of Chinese Medical Association, Eye Trauma Group of Ophthalmology Branch of Chinese Medical Association, Glaucoma Group of Ophthalmology Branch of Chinese Medical Association. Chinese expert consensus on the diagnosis and management of infectious endophthalmitis after ophthalmic surgery (2022)[J]. Chin J Ophthalmol, 2022, 58(7): 487-499. DOI: 10.3760/cma.j.cn112142-20220301-00088.
28.	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[J]. Lancet, 2017, 390(10097): 849-860. DOI: 10.1016/S0140-6736(17)31868-8.

1. Sullivan LS, Daiger SP. Inherited retinal degeneration: exceptional genetic and clinical heterogeneity[J]. Mol Med Today, 1996, 2(9): 380-386. DOI: 10.1016/s1357-4310(96)10037-x.
2. Xu L, Hu L, Ma K, et al. Prevalence of retinitis pigmentosa in urban and rural adult Chinese: The Beijing Eye Study[J]. Eur J Ophthalmol, 2006, 16(6): 865-866. DOI: 10.1177/112067210601600614.
3. 國家發展和改革委員會. 中華人民共和國國民經濟和社會發展第十四個五年規劃和2035年遠景目標綱要[EB/OL]. (2021-03-12)[2022-08-08]. http://www.gov.cn/xinwen/2021-03/13/content_5592681.htm.National Development and Reform Commission. Outline of the 14th Five-Year Plan for National Economic and Social Development of the People's Republic of China and the Vision for 2035[EB/OL]. (2021-03-12)[2022-08-08]. http://www.gov.cn/xinwen/2021-03/13/content_5592681.htm.
4. 上海市人民政府辦公廳. 上海市先進制造業發展“十四五”規劃(第12號)[EB/OL]. (2021-07-05)[2022-08-08]. https://www.shanghai.gov.cn/nw12344/20210714/0a62ea7944d34f968ccbc49eec47dbca.html.General Office of Shanghai Municipal People's Government. "14th Five-Year Plan" for the Development of Advanced Manufacturing Industry in Shanghai (No. 12)[EB/OL]. (2021-07-05)[2022-08-08]. https://www.shanghai.gov.cn/nw12344/20210714/0a62ea7944d34f968ccbc49eec47dbca.html.
5. 北京市人民政府辦公廳. 北京市“十四五”時期高精尖產業發展規劃(第21號)[EB/OL]. (2021-08-11)[2022-08-08]. http://www.beijing.gov.cn/zhengce/zhengcefagui/202108/t20210818_2471375.html.General Office of Beijing Municipal People's Government. Beijing's "14th Five-Year Plan" period high-tech industry development plan (No. 21)[EB/OL]. (2021-08-11)[2022-08-08]. http://www.beijing.gov.cn/zhengce/zhengcefagui/202108/t20210818_2471375.html.
6. Hinderer C, Katz N, Buza EL, et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN[J]. Hum Gene Ther, 2018, 29(3): 285-298. DOI: 10.1089/hum.2018.015.
7. Philippidis A. Fourth boy dies in clinical trial of Astellas' AT132[J]. Hum Gene Ther, 2021, 32(19-20): 1008-1010. DOI: 10.1089/hum.2021.29182.bfs.
8. Greenberg B, Butler J, Felker GM, et al. Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure[J]. Gene Ther, 2016, 23(3): 313-319. DOI: 10.1038/gt.2015.109.
9. 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.
10. Boyd RF, Boye SL, Conlon TJ, et al. Reduced retinal transduction and enhanced transgene-directed immunogenicity with intravitreal delivery of rAAV following posterior vitrectomy in dogs[J]. Gene Ther, 2016, 23(6): 548-556. DOI: 10.1038/gt.2016.31.
11. 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[J]. JAMA Ophthalmol, 2019, 137(11): 1247-1254. DOI: 10.1001/jamaophthalmol.2019.3278.
12. Ye GJ, Budzynski E, Sonnentag P, et al. Safety and biodistribution evaluation in cynomolgus macaques of rAAV2tYF-PR1.7-hCNGB3, a recombinant AAV vector for treatment of achromatopsia[J]. Hum Gene Ther Clin Dev, 2016, 27(1): 37-48. DOI: 10.1089/humc.2015.164.
13. 國家藥監局藥審中心. 罕見疾病藥物臨床研發技術指導原則(第71號)[EB/OL]. (2022-01-06)[2022-08-08]. https://www.nmpa.gov.cn/xxgk/fgwj/gzwj/gzwjyp/20220601110541120.html.Drug Evaluation Center of the State Food and Drug Administration. Technical Guidelines for Clinical Research and Development of Rare Disease Drugs (No. 71)[EB/OL]. (2022-01-06)[2022-08-08]. https://www.nmpa.gov.cn/xxgk/fgwj/gzwj/gzwjyp/20220601110541120.html.
14. 中國眼遺傳病診療小組, 中國眼科遺傳聯盟. 眼遺傳病基因診斷方法專家共識[J]. 中華實驗眼科雜志, 2018, 36(7): 481-488. DOI: 10.3760/cma.j.issn.2095-0160.2018.07.001.Chinese Eye Genetic Diseases Diagnosis and Treatment Group, China Eye Genetics Alliance. Expert consensus on genetic diagnosis methods for eye genetic diseases[J]. Chin J Exp Ophthalmol, 2018, 36(7): 481-488. DOI: 10.3760/cma.j.issn.2095-0160.2018.07.001.
15. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis[J]. N Engl J Med, 2008, 358(21): 2231-2239. DOI: 10.1056/NEJMoa0802268.
16. 彭曉燕, 張永鵬. 正確合理使用糖皮質激素: 一個眼底病治療中仍需重視的問題[J]. 中華眼底病雜志, 2011, 27(3): 207-209. DOI: 10.3760/cma.j.issn.1005-1015.2011.03.002.Peng XY, Zhang YP. Think twice before you go: some issues of corticosteroid application in the treatment of ocular fundus diseases[J]. Chin J Ocul Fundus Dis, 2011, 27(3): 207-209. DOI: 10.3760/cma.j.issn.1005-1015.2011.03.002.
17. 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[J]. Lancet, 2009, 374(9701): 1597-1605. DOI: 10.1016/S0140-6736(09)61836-5.
18. 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[J]. Ophthalmology, 2019, 126(9): 1273-1285. DOI: 10.1016/j.ophtha.2019.06.017.
19. Bucher K, Rodríguez-Bocanegra E, Dauletbekov D, et al. Immune responses to retinal gene therapy using adeno-associated viral vectors-implications for treatment success and safety[J/OL]. Prog Retin Eye Res, 2021, 83: 100915[2020-10-15]. https://pubmed.ncbi.nlm.nih.gov/33069860/. DOI: 10.1016/j.preteyeres.2020.100915.
20. Cideciyan AV, Jacobson SG, Drack AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect[J]. Nat Med, 2019, 25(2): 225-228. DOI: 10.1038/s41591-018-0295-0.
21. Nussenblatt RB, Palestine AG, Chan CC, et al. Standardization of vitreal inflammatory activity in intermediate and posterior uveitis[J]. Ophthalmology, 1985, 92(4): 467-471. DOI: 10.1016/s0161-6420(85)34001-0.
22. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop[J]. Am J Ophthalmol, 2005, 140(3): 509-516. DOI: 10.1016/j.ajo.2005.03.057.
23. Bouquet C, Vignal Clermont C, Galy A, et al. Immune response and intraocular inflammation in patients with Leber hereditary optic neuropathy treated with intravitreal injection of recombinant adeno-associated virus 2 carrying the ND4 gene: a secondary analysis of a phase 1/2 clinical trial[J]. JAMA Ophthalmol, 2019, 137(4): 399-406. DOI: 10.1001/jamaophthalmol.2018.6902.
24. 楊培增. 關注我國葡萄膜炎的病因和類型的變化[J]. 中華眼科雜志, 2008, 44(10): 865-866. DOI: 10.3321/j.issn:0412-4081.2008.10.001.Yang PZ. Concern on the changes of clinical pattern and etiological factors in uveitis in China[J]. Chin J Ophthalmol, 2008, 44(10): 865-866. DOI: 10.3321/j.issn:0412-4081.2008.10.001.
25. 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.
26. Gange WS, Sisk RA, Besirli CG, et al. Perifoveal chorioretinal atrophy after subretinal voretigene neparvovec-rzyl for RPE65-mediated Leber congenital amaurosis[J]. Ophthalmol Retina, 2022, 6(1): 58-64. DOI: 10.1016/j.oret.2021.03.016.
27. 中華醫學會眼科學分會眼底病學組, 中華醫學會眼科學分會白內障及屈光手術學組中華醫學會眼科學分會眼外傷學組, 中華醫學會眼科學分會青光眼學組. 中國眼科手術后感染性眼內炎診療專家共識(2022年)[J]. 中華眼科雜志, 2022, 58(7): 487-499. DOI: 10.3760/cma.j.cn112142-20220301-00088.Fundus Diseases Group of Ophthalmology Branch of Chinese Medical Association, Cataract and Refractive Surgery Group of Ophthalmology Branch of Chinese Medical Association, Eye Trauma Group of Ophthalmology Branch of Chinese Medical Association, Glaucoma Group of Ophthalmology Branch of Chinese Medical Association. Chinese expert consensus on the diagnosis and management of infectious endophthalmitis after ophthalmic surgery (2022)[J]. Chin J Ophthalmol, 2022, 58(7): 487-499. DOI: 10.3760/cma.j.cn112142-20220301-00088.
28. 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[J]. Lancet, 2017, 390(10097): 849-860. DOI: 10.1016/S0140-6736(17)31868-8.

Chinese Journal of Ocular Fundus Diseases

Expert consensus on the operative safety management and visual function evaluation index setting of gene therapy for inherited retinal diseases

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