Chinese expert consensus on the standardized application of multi-luminance mobility test in clinical trials for inherited retinal dystrophy_Chinese Journal of Ocular Fundus Diseases

Authors：

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

Corresponding author：

Fundus Disease Group of Ophthalmology Society of Chinese Medical Association, Email: xdsun@sjtu.edu.cn

Keywords：

Inherited retinal dystrophy; Multi-luminance mobility test; Endpoint evaluation; Clinical trial; Expert consensus

DOI：

10.3760/cma.j.cn511434-20241231-00513

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With the advancement of research on rare ocular diseases such as inherited retinal dystrophy (IRD) has advanced in recent years, especially breakthroughs in therapeutic approaches represented by cell and gene therapy, potential intervention strategies have emerged for these conditions. Establishing standardized endpoints and evaluation methods for visual function in patients with IRD has become crucial for assessing disease progression, safety, and therapeutic efficacy of innovative treatments. Best corrected visual acuity (BCVA) is widely recognized as one of the primary endpoints for assessing visual function. However, for IRD patients with severe rod photoreceptor dysfunction, who often present with profound low vision or even legal blindness, the applicability of BCVA as a traditional visual function indicator is limited. The multi-luminance mobility test (MLMT) has emerged as a functional visual assessment tool that evaluates the ability to navigate obstacle courses under varying illumination levels. By establishing graded evaluation standards, MLMT objectively quantifies the impact of lighting conditions on patients’ nobility and spatial orientation, providing a novel quantitative tool for assessing visual function in IRD clinical trials. Currently, there is a lack of unified and standardized guidelines for the use of MLMT in China, posing challenges to its implementation in practical clinical research. To address this, Ocular Fundus Disease Society of Chinese Medical Association and Chinese Medical Doctor Association convened a multidisciplinary team comprising clinical experts in genetic retinal diseases, statisticians, and optical specialists to investigate the current applications and technical characteristics of MLMT, ultimately formulating consensus recommendations for its use as a clinical trial endpoint for IRD gene therapies. This consensus aims to provide a set of MLMT operating norms applicable to China's national conditions, guide clinical practice and research in ophthalmology and related disciplines, and promote the standardization process of IRD clinical trials in China, so as to better serve the IRD patient population and promote the development of related fields.

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7.	Pierce EA, Aleman TS, Jayasundera KT, et al. Gene editing for CEP290-associated retinal degeneration[J]. N Engl J Med, 2024, 390(21): 1972-1984. DOI: 10.1056/NEJMoa2309915.
8.	Yang P, Pardon LP, Ho AC, et al. Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study[J]. Lancet, 2024, 404(10456): 962-970. DOI: 10.1016/S0140-6736(24)01447-8.
9.	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.
10.	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.
11.	中华医学会眼科学分会眼底病学组, 中国医师协会眼科医师分会眼底病专业委员会. 中国遗传性视网膜疾病临床试验视觉功能评估及终点指标推荐专家共识[J]. 中华眼底病杂志, 2022, 38(8): 626-635. DOI: 10.3760/cma.j.cn511434-20220808-00443.Fundus Disease Group, Ophthalmology Branch of Chinese Medical Association, and Fundus Disease Professional Committee of Ophthalmology branch of Chinese Medical Doctor Association. Expert consensus and recommendations on the evaluation of visual function and outcome measurements in clinical trials for inherited retinal diseases in China[J]. Chin J Ocul Fundus Dis, 2022, 38(8): 626-635. DOI: 10.3760/cma.j.cn511434-20220808-00443.
12.	中华人民共和国司法部司法鉴定管理局. SF/Z JD0103004-2016视觉功能障碍法医学鉴定规范[S]. 2016.Administration of Judicial Expertise, Ministry of Justice, PRC. SF/Z JD0103004-2016 Standard for forensic medical identification of visual dysfunction[S]. 2016.
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15.	Chung DC, McCague S, Yu ZF, et al. Novel mobility test to assess functional vision in patients with inherited retinal dystrophies[J]. Clin Exp Ophthalmol, 2018, 46(3): 247-259. DOI: 10.1111/ceo.13022.
16.	Jung R, Kempf M, Holocher S, et al. Multi-luminance mobility testing after gene therapy in the context of retinal functional diagnostics[J]. Graefe's Arch Clin Exp Ophthalmol, 2024, 262(2): 601-607. DOI: 10.1007/s00417-023-06237-4.
17.	Kumaran N, Ali RR, Tyler NA, et al. Validation of a vision-guided mobility assessment for RPE65-associated retinal dystrophy[J]. Transl Vis Sci Technol, 2020, 9(10): 5. DOI: 10.1167/tvst.9.10.5.
18.	陈耀龙, 杨克虎, 王小钦, 等. 中国制订/修订临床诊疗指南的指导原则(2022版)[J]. 中华医学杂志, 2022, 102(10): 697-703. DOI: 10.3760/cma.j.cn112137-20211228-02911.Chen YL, Yang KH, Wang XQ, et al. China's guiding principles for formulating/revising clinical guidelines (2022 edition)[J]. Natl Med J China, 2022, 102(10): 697-703. DOI: 10.3760/cma.j.cn112137-20211228-02911.
19.	Aleman TS, Miller AJ, Maguire KH, et al. A virtual reality orientation and mobility test for inherited retinal degenerations: testing a proof-of-concept after gene therapy[J]. Clin Ophthalmol, 2021, 15: 939-952. DOI: 10.2147/OPTH.S292527.
20.	国家市场监督管理总局. 市场监管总局关于调整实施强制管理的计量器具目录的公告(2020年第42号)[EB/OL]. (2020-10-26)[2024-12-17]. https://www.samr.gov.cn/zw/zfxxgk/fdzdgknr/jjjzs/art/2023/art_d095685b12544ed3aa6dbc3aaf7c136e.html.State Administration for Market Regulation. Announcement of the State Administration for Market Regulation on adjusting the catalogue of measuring instruments subject to compulsory management (No. 42 of 2020)[EB/OL]. (2020-10-26)[2024-12-17]. https://www.samr.gov.cn/zw/zfxxgk/fdzdgknr/jjjzs/art/2023/art_d095685b12544ed3aa6dbc3aaf7c136e.html.
21.	国家食品药品监督管理总局. 医疗器械使用质量监督管理办法[EB/OL]. (2015-10-21)[2024-12-17]. https://www.gov.cn/gongbao/content/2016/content_5033899.htm.State Food and Drug Administration. Measures for the supervision and Administration of the use quality of medical devices[EB/OL]. (2015-10-21)[2024-12-17]. https://www.gov.cn/gongbao/content/2016/content_5033899.htm.
22.	Humayun MS, Dorn JD, da Cruz L, et al. Interim results from the international trial of Second Sight's visual prosthesis[J]. Ophthalmology, 2012, 119(4): 779-788. DOI: 10.1016/j.ophtha.2011.09.028.
23.	国家药品监督管理局, 中华人民共和国国家卫生健康委员会. 药物临床试验质量管理规范[EB/OL]. (2020-04-23)[2024-12-17]. https://www.gov.cn/gongbao/content/2020/content_5525106.htm.State Drug Administration, National Health Commission of the People's Republic of China. Good quality management for drug clinical trials[EB/OL]. (2020-04-23)[2024-12-17]. https://www.gov.cn/gongbao/content/2020/content_5525106.htm.

1. Schneider N, Sundaresan Y, Gopalakrishnan P, et al. Inherited retinal diseases: linking genes, disease-causing variants, and relevant therapeutic modalities[J/OL]. Prog Retin Eye Res, 2021, 89: 101029[2021-11-25]. https://pubmed.ncbi.nlm.nih.gov/34839010/. DOI: 10.1016/j.preteyeres.2021.101029.
2. Georgiou M, Robson AG, Fujinami K, et al. Phenotyping and genotyping inherited retinal diseases: molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes[J/OL]. Prog Retin Eye Res, 2024, 100: 101244[2024-01-24]. https://pubmed.ncbi.nlm.nih.gov/38278208/. DOI: 10.1016/j.preteyeres.2024.101244.
3. den Hollander AI, Roepman R, Koenekoop RK, et al. Leber congenital amaurosis: genes, proteins and disease mechanisms[J]. Prog Retin Eye Res, 2008, 27(4): 391-419. DOI: 10.1016/j.preteyeres.2008.05.003.
4. 中国眼遗传病诊疗小组, 中国眼科遗传联盟. Leber先天黑矇诊疗的中国专家共识(2023)[J]. 中华实验眼科杂志, 2023, 41(9): 833-842. DOI: 10.3760/cma.j.cn115989-20230523-00188.Chinese Hereditary Ocular Disease Diagnosis and Treatment Group, Chinese Hereditary Ocular Disease Alliance. Chinese expert consensus on diagnosis and treatment of Leber congenital amaurosis (2023)[J]. Chin J Exp Ophthalmol, 2023, 41(9): 833-842. DOI: 10.3760/cma.j.cn115989-20230523-00188.
5. 张晓慧, 李杨. 视锥细胞营养不良及锥-杆营养不良相关基因研究进展[J]. 国际眼科纵览, 2006, 30(6): 368-372. DOI: 10.3760/cma.j.issn.1673-5803.2006.06.003.Zhang XH, Li Y. Genetics of cone dystrophy and cone-rod dystrophy[J]. Int Rev Ophthalmol, 2006, 30(6): 368-372. DOI: 10.3760/cma.j.issn.1673-5803.2006.06.003.
6. 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.
7. Pierce EA, Aleman TS, Jayasundera KT, et al. Gene editing for CEP290-associated retinal degeneration[J]. N Engl J Med, 2024, 390(21): 1972-1984. DOI: 10.1056/NEJMoa2309915.
8. Yang P, Pardon LP, Ho AC, et al. Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study[J]. Lancet, 2024, 404(10456): 962-970. DOI: 10.1016/S0140-6736(24)01447-8.
9. 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.
10. 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.
11. 中华医学会眼科学分会眼底病学组, 中国医师协会眼科医师分会眼底病专业委员会. 中国遗传性视网膜疾病临床试验视觉功能评估及终点指标推荐专家共识[J]. 中华眼底病杂志, 2022, 38(8): 626-635. DOI: 10.3760/cma.j.cn511434-20220808-00443.Fundus Disease Group, Ophthalmology Branch of Chinese Medical Association, and Fundus Disease Professional Committee of Ophthalmology branch of Chinese Medical Doctor Association. Expert consensus and recommendations on the evaluation of visual function and outcome measurements in clinical trials for inherited retinal diseases in China[J]. Chin J Ocul Fundus Dis, 2022, 38(8): 626-635. DOI: 10.3760/cma.j.cn511434-20220808-00443.
12. 中华人民共和国司法部司法鉴定管理局. SF/Z JD0103004-2016视觉功能障碍法医学鉴定规范[S]. 2016.Administration of Judicial Expertise, Ministry of Justice, PRC. SF/Z JD0103004-2016 Standard for forensic medical identification of visual dysfunction[S]. 2016.
13. Food and Drug Administration. Human gene therapy for retinal disorders[EB/OL]. (2020-01-01)[2024-12-17]. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/human-gene-therapy-retinal-disorders.
14. Chung DC, Bertelsen M, Lorenz B, et al. The natural history of inherited retinal dystrophy due to biallelic mutations in the RPE65 gene[J]. Am J Ophthalmol, 2019, 199: 58-70. DOI: 10.1016/j.ajo.2018.09.024.
15. Chung DC, McCague S, Yu ZF, et al. Novel mobility test to assess functional vision in patients with inherited retinal dystrophies[J]. Clin Exp Ophthalmol, 2018, 46(3): 247-259. DOI: 10.1111/ceo.13022.
16. Jung R, Kempf M, Holocher S, et al. Multi-luminance mobility testing after gene therapy in the context of retinal functional diagnostics[J]. Graefe's Arch Clin Exp Ophthalmol, 2024, 262(2): 601-607. DOI: 10.1007/s00417-023-06237-4.
17. Kumaran N, Ali RR, Tyler NA, et al. Validation of a vision-guided mobility assessment for RPE65-associated retinal dystrophy[J]. Transl Vis Sci Technol, 2020, 9(10): 5. DOI: 10.1167/tvst.9.10.5.
18. 陈耀龙, 杨克虎, 王小钦, 等. 中国制订/修订临床诊疗指南的指导原则(2022版)[J]. 中华医学杂志, 2022, 102(10): 697-703. DOI: 10.3760/cma.j.cn112137-20211228-02911.Chen YL, Yang KH, Wang XQ, et al. China's guiding principles for formulating/revising clinical guidelines (2022 edition)[J]. Natl Med J China, 2022, 102(10): 697-703. DOI: 10.3760/cma.j.cn112137-20211228-02911.
19. Aleman TS, Miller AJ, Maguire KH, et al. A virtual reality orientation and mobility test for inherited retinal degenerations: testing a proof-of-concept after gene therapy[J]. Clin Ophthalmol, 2021, 15: 939-952. DOI: 10.2147/OPTH.S292527.
20. 国家市场监督管理总局. 市场监管总局关于调整实施强制管理的计量器具目录的公告(2020年第42号)[EB/OL]. (2020-10-26)[2024-12-17]. https://www.samr.gov.cn/zw/zfxxgk/fdzdgknr/jjjzs/art/2023/art_d095685b12544ed3aa6dbc3aaf7c136e.html.State Administration for Market Regulation. Announcement of the State Administration for Market Regulation on adjusting the catalogue of measuring instruments subject to compulsory management (No. 42 of 2020)[EB/OL]. (2020-10-26)[2024-12-17]. https://www.samr.gov.cn/zw/zfxxgk/fdzdgknr/jjjzs/art/2023/art_d095685b12544ed3aa6dbc3aaf7c136e.html.
21. 国家食品药品监督管理总局. 医疗器械使用质量监督管理办法[EB/OL]. (2015-10-21)[2024-12-17]. https://www.gov.cn/gongbao/content/2016/content_5033899.htm.State Food and Drug Administration. Measures for the supervision and Administration of the use quality of medical devices[EB/OL]. (2015-10-21)[2024-12-17]. https://www.gov.cn/gongbao/content/2016/content_5033899.htm.
22. Humayun MS, Dorn JD, da Cruz L, et al. Interim results from the international trial of Second Sight's visual prosthesis[J]. Ophthalmology, 2012, 119(4): 779-788. DOI: 10.1016/j.ophtha.2011.09.028.
23. 国家药品监督管理局, 中华人民共和国国家卫生健康委员会. 药物临床试验质量管理规范[EB/OL]. (2020-04-23)[2024-12-17]. https://www.gov.cn/gongbao/content/2020/content_5525106.htm.State Drug Administration, National Health Commission of the People's Republic of China. Good quality management for drug clinical trials[EB/OL]. (2020-04-23)[2024-12-17]. https://www.gov.cn/gongbao/content/2020/content_5525106.htm.

Chinese Journal of Ocular Fundus Diseases

Latest ArticlesChinese expert consensus on the standardized application of multi-luminance mobility test in clinical trials for inherited retinal dystrophy

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