Changes of visual acuity and visual evoked potentials before and after gene therapy for Leber hereditary optic neuropathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Yang Xueying ¹ ,  Chen Changzheng ¹ , Yuan Jiajia ¹ , Li Bin ^2,3

1. Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan 430060, China;
2. Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
3. Wuhan Newforth Biotechnology Co., Ltd, Wuhan 430040, China;

Corresponding?author：

Chen Changzheng, Email: whuchenchzh@163.com

Keywords：

Optic atrophy, hereditary, Leber; Evoked potential, visual; Gene therapy

DOI：

10.3760/cma.j.cn511434-20210106-00006

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Objective To observe the changes of vision and visual evoked potentials (VEP) in patients with Leber hereditary optic neuropathy (LHON) before and after gene therapy.Methods A retrospective cohort study. From December 2017 to October 2018, 35 cases of 70 eyes of m11778G.A/MT-ND4 mutant LHON patients who were diagnosed in the Tongji Hospital of Huazhong University of Science and Technology and received gene therapy were included in the study. There were 30 males (87.71%) and 5 females (12.29%), with the mean age of 23.31±6.72 years. The gene therapy method was intravitreal injection of rAAV2-ND4 (recombinant adeno-associated virus carrying NADH-ubiquinone oxidoreductase subunit 4 gene) into one eye. The eye with poor visual acuity was chosen as the injection eye. If both eyes had the same visual acuity, the right eye was designated as the injection eye. Seventy eyes were divided into the injected eye group and the non-injected eye group, in which were both 35 eyes. The best corrected visual acuity (BCVA) and pattern VEP (PVEP) examinations were performed in the injected eye group and the non-injected eye group before treatment (baseline), 1, 3, and 6 months after injection. Compare the changes of BCVA and PVEP between the injected eye group and the non-injected eye group at baseline, 1 month, 3 months, and 6 months after injection. Independent sample t test, paired sample t test or two independent sample nonparametric test were performed to compare the two groups.Results Compared with baseline, 1, 3, and 6 months after treatment, the BCVA of the injected eye group (t=3.530, 4.962, 5.281; P=0.001, 0.000, 0.000) and the non-injected eye group (t=3.288, 2.620, 2.252; P= 0.002, 0.013, 0.031) increased, and the difference was statistically significant; there was no statistically significant difference between VEP IT (t_injected_{eye group}=?0.158, 1.046, ?1.134; P_injected_{eye group} = 0.875, 0.303, 0.190; t_non_{-injected eye group}=0.773, ?0.607, ?0.944; P_non_{-injected eye group}= 0.445, 0.548, 0.352) and VEP A (Z_injected_{eye group}=?0.504, ?0.934, ?1.065; P_injected_{eye group}= 0.614, 0.351, 0.287; Z_non_{-injected eye group}=?0.521, ?0.115, ?0.491; P_non_{-injected eye group} = 0.602, 0.909, 0.623).Conclusion After gene therapy, the visual acuity of the injected and non-injected eyes of LHON patients improved; PVEP did not change significantly, and remained stable compared with baseline.

Citation： Yang Xueying, Chen Changzheng, Yuan Jiajia, Li Bin. Changes of visual acuity and visual evoked potentials before and after gene therapy for Leber hereditary optic neuropathy. Chinese Journal of Ocular Fundus Diseases, 2021, 37(3): 189-194. doi: 10.3760/cma.j.cn511434-20210106-00006 Copy

1.	Parisi V, Ziccardi L, Sadun F, et al. Functional changes of retinal ganglion cells and visual pathways in patients with chronic Leber’s hereditary optic neuropathy during one year of follow-up[J]. Ophthalmology, 2019, 126(7): 1033-1044. DOI: 10.1016/j.ophtha.2019.02.018.
2.	Yen MY, Wang AG, Wei YH. Leber's hereditary optic neuropathy: a multifactorial disease[J]. Prog Retin Eye Res, 2006, 25(4): 381-396. DOI: 10.1016/j.preteyeres.2006.05.002.
3.	Majander A, Robson AG, Jo?o C, et al. The pattern of retinal ganglion cell dysfunction in Leber hereditary optic neuropathy[J]. Mitochondrion, 2017, 36: 138-149. DOI: 10.1016/j.mito.2017.07.006.
4.	Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies-disease mechanisms and therapeutic strategies[J]. Prog Retin Eye Res, 2011, 30(2): 81-114. DOI: 10.1016/j.preteyeres.2010.11.002.
5.	韋企平, 孫艷紅, 宮曉紅, 等. 中國人Leber遺傳性視神經病變線粒體DNA突變的主要類型和臨床特征[J]. 中華眼底病雜志, 2004, 20(2): 78-80.Wei QP, Sun YH, Gong XH, et al. The major types and clinical manifestations of mitochondrial DNA mutations in Chinese patients with Leber′s hereditary optic neuropathy[J]. Chin J Ocul Fundus Dis, 2004, 20(2): 78-80.
6.	Yang S, Ma SQ, Wan X, et al. Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy[J]. EBioMedicine, 2016, 10: 258-268. DOI: 10.1016/j.ebiom.2016.07.002.
7.	Wan X, Pei H, Zhao MJ, et al. Efficacy and safety of rAAV2-ND4 treatment for Leber’s hereditary optic neuropathy[J/OL]. Sci Rep, 2016, 6(1): 21587[2016-02-19]. http://europepmc.org/article/MED/26892229. DOI: 10.1038/srep21587.
8.	Zhang Y, Li X, Yuan JJ, et al. Prognostic factors for visual acuity in patients with Leber’s hereditary optic neuropathy after rAAV2‐ND4 gene therapy[J]. Clin Exp Ophthalmol, 2019, 47(6): 774-778. DOI: 10.1111/ceo.13515.
9.	國際臨床視覺電生理學會. 視覺電生理診斷流程指南[J]. 中華眼科雜志, 2020, 56(7): 492-508. DOI: 10.3760/cma.j.cn112142-20200217-00077.International Society for Clinical Visual Electrophysiology. Guidelines for the diagnostic process of visual electrophysiology[J]. Chin J Ophthalmol, 2020, 56(7): 492-508. DOI: 10.3760/cma.j.cn112142-20200217-00077.
10.	Yang S, Yang H, Ma SQ, et al. Evaluation of Leber?s hereditary optic neuropathy patients prior to a gene therapy clinical trial[J]. Medicine, 2016, 95(40): 1-6. DOI: 10.1097/MD.0000000000005110.
11.	Theodorou-Kanakari A, Karampitianis S, Karageorgou V, et al. Current and emerging treatment modalities for Leber’s hereditary optic neuropathy: a review of the literature[J]. Adv Ther, 2018, 35(10): 1510-1518. DOI: 10.1007/s12325-018-0776-z.
12.	陳倩, 田國紅. 視覺電生理結果的解讀[J]. 中國眼耳鼻喉科雜志, 2018, 18(1): 68-72. DOI: 10.14166/j.issn.1671-2420.2018.08.022.Chen Q, Tian GH. Interpretation of visual electrophysiological results[J]. Chin J Ophthalmol Otorhinolaryngol, 2018, 18(1): 68-72. DOI: 10.14166/j.issn.1671-2420.2018.08.022.
13.	Tai TYT. Visual evoked potentials and glaucoma[J]. Asia Pac J Ophthalmol (Phila), 2018, 7(5): 352-355. DOI: 10.22608/APO.2017532.
14.	William J, Joyce C, Janet L. Gene therapy for Leber hereditary optic neuropathy[J]. Ophthalmology, 2016, 123(3): 558-570. DOI: 10.1016/j.ophtha.2015.10.025.
15.	Liu HL, Yuan JJ, Zhang Y, et al. Factors associated with rapid improvement in visual acuity in patients with Leber's hereditary optic neuropathy after gene therapy[J]. Acta Ophthalmol, 2020, 98(6): e730-e733. DOI: 10.1111/aos.14379.
16.	Zhang Y, Yuan JJ, Liu HL, et al. Three cases of Leber's hereditary optic neuropathy with rapid increase in visual acuity after gene therapy[J]. Curr Gene Ther, 2019, 19(2): 134-138. DOI: 10.2174/1566523219666190618094505.
17.	Kousal B, Kolarova H, Meliska M, et al. Peripapillary microcirculation in Leber hereditary optic neuropathy[J]. Acta Ophthalmol, 2019, 97(1): e71-e76. DOI: 10.1111/aos.13817.
18.	Balducci N, Cascavilla ML, Ciardella A, et al. Peripapillary vessel density changes in Leber's hereditary optic neuropathy: a new biomarker[J]. Clin Exp Ophthalmol, 2018, 46(9): 1055-1062. DOI: 10.1002/ceo.13326.
19.	Wang D, Liu HL, Du YY, et al. Characterisation of thickness changes in the peripapillary retinal nerve fibre layer in patients with Leber’s hereditary optic neuropathy[J/OL]. Br J Ophthalmol, 2020, 2020: E1-6[2020-08-29]. http://bjo.bmj.com/lookup/pmidlookup?view=long&pmid=32862131. DOI: 10.1136/bjophthalmol-2020-316573. [published online ahead of print].
20.	Ziccardi L, Parisi V, Giannini D, et al. Multifocal VEP provide electrophysiological evidence of predominant dysfunction of the optic nerve fibers derived from the central retina in Leber’s hereditary optic neuropathy[J]. Graefe's Arch Clin Exp Ophthalmol, 2015, 253(9): 1591-1600. DOI: 10.1007/s00417-015-2979-1.
21.	Guy J, Feuer WJ, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy[J]. Ophthalmology, 2017, 124(11): 1621-1634. DOI: 10.1016/j.ophtha.2017.05.016.
22.	Cen LP, Ng TK, Liang JJ, et al. Human periodontal ligament-derived stem cells promote retinal ganglion cell survival and axon regeneration after optic nerve injury[J]. Stem Cells, 2018, 36(6): 844-855. DOI: 10.1002/stem.2812.
23.	Pernet V, Joly S, Dalkara D, et al. Long-distance axonal regeneration induced by CNTF gene transfer is impaired by axonal misguidance in the injured adult optic nerve[J]. Neurobiol Dis, 2013, 51: 202-213. DOI: 10.1016/j.nbd.2012.11.011.
24.	Yang S, He H, Zhu Y, et al. Chemical and material communication between the optic nerves in rats[J]. Clin Exp Ophthalmol, 2015, 43(8): 742-748. DOI: 10.1111/ceo.12547.

1. Parisi V, Ziccardi L, Sadun F, et al. Functional changes of retinal ganglion cells and visual pathways in patients with chronic Leber’s hereditary optic neuropathy during one year of follow-up[J]. Ophthalmology, 2019, 126(7): 1033-1044. DOI: 10.1016/j.ophtha.2019.02.018.
2. Yen MY, Wang AG, Wei YH. Leber's hereditary optic neuropathy: a multifactorial disease[J]. Prog Retin Eye Res, 2006, 25(4): 381-396. DOI: 10.1016/j.preteyeres.2006.05.002.
3. Majander A, Robson AG, Jo?o C, et al. The pattern of retinal ganglion cell dysfunction in Leber hereditary optic neuropathy[J]. Mitochondrion, 2017, 36: 138-149. DOI: 10.1016/j.mito.2017.07.006.
4. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies-disease mechanisms and therapeutic strategies[J]. Prog Retin Eye Res, 2011, 30(2): 81-114. DOI: 10.1016/j.preteyeres.2010.11.002.
5. 韋企平, 孫艷紅, 宮曉紅, 等. 中國人Leber遺傳性視神經病變線粒體DNA突變的主要類型和臨床特征[J]. 中華眼底病雜志, 2004, 20(2): 78-80.Wei QP, Sun YH, Gong XH, et al. The major types and clinical manifestations of mitochondrial DNA mutations in Chinese patients with Leber′s hereditary optic neuropathy[J]. Chin J Ocul Fundus Dis, 2004, 20(2): 78-80.
6. Yang S, Ma SQ, Wan X, et al. Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy[J]. EBioMedicine, 2016, 10: 258-268. DOI: 10.1016/j.ebiom.2016.07.002.
7. Wan X, Pei H, Zhao MJ, et al. Efficacy and safety of rAAV2-ND4 treatment for Leber’s hereditary optic neuropathy[J/OL]. Sci Rep, 2016, 6(1): 21587[2016-02-19]. http://europepmc.org/article/MED/26892229. DOI: 10.1038/srep21587.
8. Zhang Y, Li X, Yuan JJ, et al. Prognostic factors for visual acuity in patients with Leber’s hereditary optic neuropathy after rAAV2‐ND4 gene therapy[J]. Clin Exp Ophthalmol, 2019, 47(6): 774-778. DOI: 10.1111/ceo.13515.
9. 國際臨床視覺電生理學會. 視覺電生理診斷流程指南[J]. 中華眼科雜志, 2020, 56(7): 492-508. DOI: 10.3760/cma.j.cn112142-20200217-00077.International Society for Clinical Visual Electrophysiology. Guidelines for the diagnostic process of visual electrophysiology[J]. Chin J Ophthalmol, 2020, 56(7): 492-508. DOI: 10.3760/cma.j.cn112142-20200217-00077.
10. Yang S, Yang H, Ma SQ, et al. Evaluation of Leber?s hereditary optic neuropathy patients prior to a gene therapy clinical trial[J]. Medicine, 2016, 95(40): 1-6. DOI: 10.1097/MD.0000000000005110.
11. Theodorou-Kanakari A, Karampitianis S, Karageorgou V, et al. Current and emerging treatment modalities for Leber’s hereditary optic neuropathy: a review of the literature[J]. Adv Ther, 2018, 35(10): 1510-1518. DOI: 10.1007/s12325-018-0776-z.
12. 陳倩, 田國紅. 視覺電生理結果的解讀[J]. 中國眼耳鼻喉科雜志, 2018, 18(1): 68-72. DOI: 10.14166/j.issn.1671-2420.2018.08.022.Chen Q, Tian GH. Interpretation of visual electrophysiological results[J]. Chin J Ophthalmol Otorhinolaryngol, 2018, 18(1): 68-72. DOI: 10.14166/j.issn.1671-2420.2018.08.022.
13. Tai TYT. Visual evoked potentials and glaucoma[J]. Asia Pac J Ophthalmol (Phila), 2018, 7(5): 352-355. DOI: 10.22608/APO.2017532.
14. William J, Joyce C, Janet L. Gene therapy for Leber hereditary optic neuropathy[J]. Ophthalmology, 2016, 123(3): 558-570. DOI: 10.1016/j.ophtha.2015.10.025.
15. Liu HL, Yuan JJ, Zhang Y, et al. Factors associated with rapid improvement in visual acuity in patients with Leber's hereditary optic neuropathy after gene therapy[J]. Acta Ophthalmol, 2020, 98(6): e730-e733. DOI: 10.1111/aos.14379.
16. Zhang Y, Yuan JJ, Liu HL, et al. Three cases of Leber's hereditary optic neuropathy with rapid increase in visual acuity after gene therapy[J]. Curr Gene Ther, 2019, 19(2): 134-138. DOI: 10.2174/1566523219666190618094505.
17. Kousal B, Kolarova H, Meliska M, et al. Peripapillary microcirculation in Leber hereditary optic neuropathy[J]. Acta Ophthalmol, 2019, 97(1): e71-e76. DOI: 10.1111/aos.13817.
18. Balducci N, Cascavilla ML, Ciardella A, et al. Peripapillary vessel density changes in Leber's hereditary optic neuropathy: a new biomarker[J]. Clin Exp Ophthalmol, 2018, 46(9): 1055-1062. DOI: 10.1002/ceo.13326.
19. Wang D, Liu HL, Du YY, et al. Characterisation of thickness changes in the peripapillary retinal nerve fibre layer in patients with Leber’s hereditary optic neuropathy[J/OL]. Br J Ophthalmol, 2020, 2020: E1-6[2020-08-29]. http://bjo.bmj.com/lookup/pmidlookup?view=long&pmid=32862131. DOI: 10.1136/bjophthalmol-2020-316573. [published online ahead of print].
20. Ziccardi L, Parisi V, Giannini D, et al. Multifocal VEP provide electrophysiological evidence of predominant dysfunction of the optic nerve fibers derived from the central retina in Leber’s hereditary optic neuropathy[J]. Graefe's Arch Clin Exp Ophthalmol, 2015, 253(9): 1591-1600. DOI: 10.1007/s00417-015-2979-1.
21. Guy J, Feuer WJ, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy[J]. Ophthalmology, 2017, 124(11): 1621-1634. DOI: 10.1016/j.ophtha.2017.05.016.
22. Cen LP, Ng TK, Liang JJ, et al. Human periodontal ligament-derived stem cells promote retinal ganglion cell survival and axon regeneration after optic nerve injury[J]. Stem Cells, 2018, 36(6): 844-855. DOI: 10.1002/stem.2812.
23. Pernet V, Joly S, Dalkara D, et al. Long-distance axonal regeneration induced by CNTF gene transfer is impaired by axonal misguidance in the injured adult optic nerve[J]. Neurobiol Dis, 2013, 51: 202-213. DOI: 10.1016/j.nbd.2012.11.011.
24. Yang S, He H, Zhu Y, et al. Chemical and material communication between the optic nerves in rats[J]. Clin Exp Ophthalmol, 2015, 43(8): 742-748. DOI: 10.1111/ceo.12547.

Chinese Journal of Ocular Fundus Diseases

Changes of visual acuity and visual evoked potentials before and after gene therapy for Leber hereditary optic neuropathy

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