Gene therapy for Leber hereditary optic neuropathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Miao Qingmei ,  Chen Changzheng , Yuan Jiajia

Department of Ophthalmology Renmin Hospital of Wuhan University, Wuhan 430060, China;

Corresponding author：

Chen Changzheng, Email: whuchenchzh@163.com

Keywords：

Leber hereditary optic neuropathy; DNA, mitochondrial; Adeno-associated virus; Gene therapy; Review

DOI：

10.3760/cma.j.cn511434-20220127-00049

Video：

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Abstract Full text Figures/Tables Video References Cited by

Leber hereditary optic neuropathy (LHON) is a matrilineal hereditary optic neuropathy in which mitochondrial DNA mutations lead to retinal ganglion cell degeneration. At present, the treatment for LHON is limited. Early symptomatic treatment and medical treatment may improve the vision of patients. In recent years, rapid progress has been made in gene therapy. Many clinical studies have confirmed its safety and efficacy. Monocular gene therapy is helpful to improve the visual function of LHON patients, and it can also improve the visual acuity of uninjected eyes. Patients do not have serious eye or systemic adverse events during the treatment period, showing good safety and tolerance. Studies with larger sample size and longer follow-up time are needed to further verify the efficacy and safety of gene therapy in the future. Gene therapy is expected to become a safe and effective treatment, bringing hope to LHON patients.

Citation： Miao Qingmei, Chen Changzheng, Yuan Jiajia. Gene therapy for Leber hereditary optic neuropathy. Chinese Journal of Ocular Fundus Diseases, 2022, 38(12): 1031-1034. doi: 10.3760/cma.j.cn511434-20220127-00049 Copy

1.	Meyerson C, Van Stavern G, McClelland C. Leber hereditary optic neuropathy: current perspectives[J]. Clin Ophthalmol, 2015, 9: 1165-1176. DOI: 10.2147/OPTH.S62021.
2.	Achilli A, Iommarini L, Olivieri A, et al. Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy[J/OL]. PLoS One, 2012, 7(8): e42242[2012-08-03]. https://pubmed.ncbi.nlm.nih.gov/22879922/. DOI: 10.1371/journal.pone.0042242.
3.	Harding AE, Sweeney MG, Govan GG, et al. Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation[J]. Am J Hum Genet, 1995, 57(1): 77-86.
4.	Amore G, Romagnoli M, Carbonelli M, et al. Therapeutic options in hereditary optic neuropathies[J]. Drugs, 2020, 81(1): 57-86. DOI: 10.1007/s40265-020-01428-3.
5.	Zuccarelli M, Vella-Szijj J, Serracino-Inglott A, et al. Treatment of Leber's hereditary optic neuropathy: an overview of recent developments[J]. Eur J Ophthalmol, 2020, 30(6): 1220-1227. DOI: 10.1177/1120672120936592.
6.	Pemp B, Mitsch C, Kircher K, et al. Changes in visual function and correlations with inner retinal structure in acute and chronic Leber's hereditary optic neuropathy patients after treatment with idebenone[J]. J Clin Med, 2021, 10(1): 151. DOI: 10.3390/jcm10010151.
7.	Pemp B, Kircher K, Reitner A. Visual function in chronic Leber's hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset[J/OL]. Graefe's Arch Clin Exp Ophthalmol, 2019, 257(12): 2751-2757[2019-09-03]. https://pubmed.ncbi.nlm.nih.gov/31482278/. DOI: 10.1007/s00417-019-04444-6.
8.	Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy[J/OL]. Brain, 2011, 134(Pt 9): 2677-2686[2011-07-25]. https://pubmed.ncbi.nlm.nih.gov/21788663/. DOI: 10.1093/brain/awr170.
9.	Klopstock T, Metz G, Yu-Wai-Man P, et al. Persistence of the treatment effect of idebenone in Leber's hereditary optic neuropathy[J/OL]. Brain, 2013, 136(Pt 2): e230[2013-02-06]. https://pubmed.ncbi.nlm.nih.gov/23388409/. DOI: 10.1093/brain/aws279.
10.	王佳伟, 赵娟. Leber遗传性视神经病变诊断和治疗专家共识[J]. 眼科, 2019, 28(5): 328-335. DOI: 10.13281/j.cnki.issn.1004-4469.2019.05.003.Wang JW, Zhao J. Expert consensus on diagnosis and treatment of Leber hereditary optic neuropathy[J]. Ophthalmol CHN, 2019, 28(5): 328-335. DOI: 10.13281/j.cnki.issn.1004-4469.2019.05.003.
11.	Spruijt L, Kolbach DN, de Coo RF, et al. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy[J]. Am J Ophthalmol, 2006, 141(4): 676-682. DOI: 10.1016/j.ajo.2005.11.007.
12.	Koilkonda RD, Guy J. Leber's hereditary optic neuropathy-gene therapy: from benchtop to bedside[J/OL]. J Ophthalmol, 2011, 2011: 179412[2010-12-26]. https://pubmed.ncbi.nlm.nih.gov/21253496/. DOI: 10.1155/2011/179412.
13.	Yu H, Koilkonda RD, Chou TH, et al. Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber's hereditary optic neuropathy in a mouse model[J/OL]. Proc Natl Acad Sci USA, 2012, 109(20): E1238-1247[2012-04-20]. https://pubmed.ncbi.nlm.nih.gov/22523243/. DOI: 10.1073/pnas.1119577109.
14.	Collombet JM, Wheeler VC, Vogel F, et al. Introduction of plasmid DNA into isolated mitochondria by electroporation. A novel approach toward gene correction for mitochondrial disorders[J]. J Biol Chem, 1997, 272(8): 5342-5347. DOI: 10.1074/jbc.272.8.5342.
15.	Sendra L, Garcia-Mares A, Herrero MJ, et al. Mitochondrial DNA replacement techniques to prevent human mitochondrial diseases[J]. Int J Mol Sci, 2021, 22(2): 551. DOI: 10.3390/ijms22020551.
16.	Cao X, Yung J, Mak H, et al. Factors governing the transduction efficiency of adeno-associated virus in the retinal ganglion cells following intravitreal injection[J]. Gene Ther, 2019, 26(3-4): 109-120. DOI: 10.1038/s41434-019-0060-0.
17.	Langouet-Astrie CJ, Yang Z, Polisetti SM, et al. Characterization of intravitreally delivered capsid mutant AAV2-Cre vector to induce tissue-specific mutations in murine retinal ganglion cells[J]. Exp Eye Res, 2016, 151: 61-67. DOI: 10.1016/j.exer.2016.07.019.
18.	丁芝祥, 谭浅. 腺相关病毒载体在眼病基因治疗中的应用及研究进展[J]. 国际眼科杂志, 2009, 9(6): 1125-1127. DOI: 10.3969/j.issn.1672-5123.2009.06.038.Ding ZX, Tan Q. Progress in gene therapy for eye diseases using adeno-associated virus as a vector[J]. Int Eye Sci, 2009, 9(6): 1125-1127. DOI: 10.3969/j.issn.1672-5123.2009.06.038.
19.	Guy J, Qi X, Pallotti F, et al. Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy[J]. Ann Neurol, 2002, 52(5): 534-542. DOI: 10.1002/ana.10354.
20.	Sahel JA, Newman NJ, Yu-Wai-Man P, et al. Gene therapies for the treatment of Leber hereditary optic neuropathy[J]. Int Ophthalmol Clin, 2021, 61(4): 195-208. DOI: 10.1097/IIO.0000000000000364.
21.	Guy J, Qi X, Koilkonda RD, et al. Efficiency and safety of AAV-mediated gene delivery of the human ND4 complex Ⅰ subunit in the mouse visual system[J]. Invest Ophthalmol Vis Sci, 2009, 50(9): 4205-4214. DOI: 10.1167/iovs.08-3214.
22.	Shi H, Gao J, Pei H, et al. Adeno-associated virus-mediated gene delivery of the human ND4 complex Ⅰ subunit in rabbit eyes[J]. Clin Exp Ophthalmol, 2012, 40(9): 888-894. DOI: 10.1111/j.1442-9071.2012.02815.x.
23.	Koilkonda RD, Yu H, Chou TH, et al. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial[J]. JAMA Ophthalmol, 2014, 132(4): 409-420. DOI: 10.1001/jamaophthalmol.2013.7630.
24.	Yuan J, Zhang Y, Liu H, et al. Seven-year follow-up of gene therapy for Leber's hereditary optic neuropathy[J]. Ophthalmology, 2020, 127(8): 1125-1127. DOI: 10.1016/j.ophtha.2020.02.023.
25.	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: 21587[2016-02-19]. https://pubmed.ncbi.nlm.nih.gov/26892229/. DOI: 10.1038/srep21587.
26.	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.
27.	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/OL]. Acta Ophthalmol, 2020, 98(6): e730-e733[2020-02-24]. https://pubmed.ncbi.nlm.nih.gov/32096343/. DOI: 10.1111/aos.14379.
28.	Zhang Y, Li X, Yuan J, 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.
29.	Feuer WJ, Schiffman JC, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: initial results[J]. Ophthalmology, 2016, 123(3): 558-570. DOI: 10.1016/j.ophtha.2015.10.025.
30.	Vignal C, Uretsky S, Fitoussi S, et al. Safety of rAAV2/2-ND4 gene therapy for Leber hereditary optic neuropathy[J]. Ophthalmology, 2018, 125(6): 945-947. DOI: 10.1016/j.ophtha.2017.12.036.
31.	Vignal-Clermont C, Girmens JF, Audo I, et al. Safety of intravitreal gene therapy for treatment of subjects with Leber hereditary optic neuropathy due to mutations in the mitochondrial ND4 gene: The REVEAL Study[J]. BioDrugs, 2021, 35(2): 201-214. DOI: 10.1007/s40259-021-00468-9.
32.	Newman NJ, Yu-Wai-Man P, Carelli V, et al. Efficacy and safety of intravitreal gene therapy for Leber hereditary optic neuropathy treated within 6 months of disease onset[J]. Ophthalmology, 2021, 128(5): 649-660. DOI: 10.1016/j.ophtha.2020.12.012.
33.	Yu-Wai-Man P, Newman N J, Carelli V, et al. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy[J/OL]. Sci Transl Med, 2020, 12(573): e7423[2020-12-09]. https://pubmed.ncbi.nlm.nih.gov/33298565/. DOI: 10.1126/scitranslmed.aaz7423.
34.	Biousse V, Newman NJ, Yu-Wai-Man P, et al. Long-term follow-up after unilateral intravitreal gene therapy for Leber hereditary optic neuropathy: The RESTORE Study[J]. J Neuroophthalmol, 2021, 41(3): 309-315. DOI: 10.1097/WNO.0000000000001367.
35.	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.
36.	Zingg B, Chou XL, Zhang ZG, et al. AAV-mediated anterograde transsynaptic tagging: mapping corticocollicular input-defined neural pathways for defense behaviors[J]. Neuron, 2017, 93(1): 33-47. DOI: 10.1016/j.neuron.2016.11.045.
37.	Yang S, Chen C, Yuan JJ, et al. Multilocus mitochondrial mutations do not directly affect the efficacy of gene therapy for Leber hereditary optic neuropathy[J]. J Neuroophthalmol, 2020, 40(1): 22-29. DOI: 10.1097/WNO.0000000000000797.
38.	Guy J, Feuer WJ, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: low- and medium-dose visual results[J]. Ophthalmology, 2017, 124(11): 1621-1634. DOI: 10.1016/j.ophtha.2017.05.016.
39.	Duncan JL. Understanding ocular inflammation in eyes treated with intravitreal gene therapy[J]. JAMA Ophthalmol, 2019, 137(4): 407. DOI: 10.1001/jamaophthalmol.2018.6902.
40.	Yang X, Jiang J, Li Z, et al. Strategies for mitochondrial gene editing[J]. Comput Struct Biotechnol J, 2021, 19: 3319-3329. DOI: 10.1016/j.csbj.2021.06.003.

1. Meyerson C, Van Stavern G, McClelland C. Leber hereditary optic neuropathy: current perspectives[J]. Clin Ophthalmol, 2015, 9: 1165-1176. DOI: 10.2147/OPTH.S62021.
2. Achilli A, Iommarini L, Olivieri A, et al. Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy[J/OL]. PLoS One, 2012, 7(8): e42242[2012-08-03]. https://pubmed.ncbi.nlm.nih.gov/22879922/. DOI: 10.1371/journal.pone.0042242.
3. Harding AE, Sweeney MG, Govan GG, et al. Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation[J]. Am J Hum Genet, 1995, 57(1): 77-86.
4. Amore G, Romagnoli M, Carbonelli M, et al. Therapeutic options in hereditary optic neuropathies[J]. Drugs, 2020, 81(1): 57-86. DOI: 10.1007/s40265-020-01428-3.
5. Zuccarelli M, Vella-Szijj J, Serracino-Inglott A, et al. Treatment of Leber's hereditary optic neuropathy: an overview of recent developments[J]. Eur J Ophthalmol, 2020, 30(6): 1220-1227. DOI: 10.1177/1120672120936592.
6. Pemp B, Mitsch C, Kircher K, et al. Changes in visual function and correlations with inner retinal structure in acute and chronic Leber's hereditary optic neuropathy patients after treatment with idebenone[J]. J Clin Med, 2021, 10(1): 151. DOI: 10.3390/jcm10010151.
7. Pemp B, Kircher K, Reitner A. Visual function in chronic Leber's hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset[J/OL]. Graefe's Arch Clin Exp Ophthalmol, 2019, 257(12): 2751-2757[2019-09-03]. https://pubmed.ncbi.nlm.nih.gov/31482278/. DOI: 10.1007/s00417-019-04444-6.
8. Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy[J/OL]. Brain, 2011, 134(Pt 9): 2677-2686[2011-07-25]. https://pubmed.ncbi.nlm.nih.gov/21788663/. DOI: 10.1093/brain/awr170.
9. Klopstock T, Metz G, Yu-Wai-Man P, et al. Persistence of the treatment effect of idebenone in Leber's hereditary optic neuropathy[J/OL]. Brain, 2013, 136(Pt 2): e230[2013-02-06]. https://pubmed.ncbi.nlm.nih.gov/23388409/. DOI: 10.1093/brain/aws279.
10. 王佳伟, 赵娟. Leber遗传性视神经病变诊断和治疗专家共识[J]. 眼科, 2019, 28(5): 328-335. DOI: 10.13281/j.cnki.issn.1004-4469.2019.05.003.Wang JW, Zhao J. Expert consensus on diagnosis and treatment of Leber hereditary optic neuropathy[J]. Ophthalmol CHN, 2019, 28(5): 328-335. DOI: 10.13281/j.cnki.issn.1004-4469.2019.05.003.
11. Spruijt L, Kolbach DN, de Coo RF, et al. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy[J]. Am J Ophthalmol, 2006, 141(4): 676-682. DOI: 10.1016/j.ajo.2005.11.007.
12. Koilkonda RD, Guy J. Leber's hereditary optic neuropathy-gene therapy: from benchtop to bedside[J/OL]. J Ophthalmol, 2011, 2011: 179412[2010-12-26]. https://pubmed.ncbi.nlm.nih.gov/21253496/. DOI: 10.1155/2011/179412.
13. Yu H, Koilkonda RD, Chou TH, et al. Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber's hereditary optic neuropathy in a mouse model[J/OL]. Proc Natl Acad Sci USA, 2012, 109(20): E1238-1247[2012-04-20]. https://pubmed.ncbi.nlm.nih.gov/22523243/. DOI: 10.1073/pnas.1119577109.
14. Collombet JM, Wheeler VC, Vogel F, et al. Introduction of plasmid DNA into isolated mitochondria by electroporation. A novel approach toward gene correction for mitochondrial disorders[J]. J Biol Chem, 1997, 272(8): 5342-5347. DOI: 10.1074/jbc.272.8.5342.
15. Sendra L, Garcia-Mares A, Herrero MJ, et al. Mitochondrial DNA replacement techniques to prevent human mitochondrial diseases[J]. Int J Mol Sci, 2021, 22(2): 551. DOI: 10.3390/ijms22020551.
16. Cao X, Yung J, Mak H, et al. Factors governing the transduction efficiency of adeno-associated virus in the retinal ganglion cells following intravitreal injection[J]. Gene Ther, 2019, 26(3-4): 109-120. DOI: 10.1038/s41434-019-0060-0.
17. Langouet-Astrie CJ, Yang Z, Polisetti SM, et al. Characterization of intravitreally delivered capsid mutant AAV2-Cre vector to induce tissue-specific mutations in murine retinal ganglion cells[J]. Exp Eye Res, 2016, 151: 61-67. DOI: 10.1016/j.exer.2016.07.019.
18. 丁芝祥, 谭浅. 腺相关病毒载体在眼病基因治疗中的应用及研究进展[J]. 国际眼科杂志, 2009, 9(6): 1125-1127. DOI: 10.3969/j.issn.1672-5123.2009.06.038.Ding ZX, Tan Q. Progress in gene therapy for eye diseases using adeno-associated virus as a vector[J]. Int Eye Sci, 2009, 9(6): 1125-1127. DOI: 10.3969/j.issn.1672-5123.2009.06.038.
19. Guy J, Qi X, Pallotti F, et al. Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy[J]. Ann Neurol, 2002, 52(5): 534-542. DOI: 10.1002/ana.10354.
20. Sahel JA, Newman NJ, Yu-Wai-Man P, et al. Gene therapies for the treatment of Leber hereditary optic neuropathy[J]. Int Ophthalmol Clin, 2021, 61(4): 195-208. DOI: 10.1097/IIO.0000000000000364.
21. Guy J, Qi X, Koilkonda RD, et al. Efficiency and safety of AAV-mediated gene delivery of the human ND4 complex Ⅰ subunit in the mouse visual system[J]. Invest Ophthalmol Vis Sci, 2009, 50(9): 4205-4214. DOI: 10.1167/iovs.08-3214.
22. Shi H, Gao J, Pei H, et al. Adeno-associated virus-mediated gene delivery of the human ND4 complex Ⅰ subunit in rabbit eyes[J]. Clin Exp Ophthalmol, 2012, 40(9): 888-894. DOI: 10.1111/j.1442-9071.2012.02815.x.
23. Koilkonda RD, Yu H, Chou TH, et al. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial[J]. JAMA Ophthalmol, 2014, 132(4): 409-420. DOI: 10.1001/jamaophthalmol.2013.7630.
24. Yuan J, Zhang Y, Liu H, et al. Seven-year follow-up of gene therapy for Leber's hereditary optic neuropathy[J]. Ophthalmology, 2020, 127(8): 1125-1127. DOI: 10.1016/j.ophtha.2020.02.023.
25. 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: 21587[2016-02-19]. https://pubmed.ncbi.nlm.nih.gov/26892229/. DOI: 10.1038/srep21587.
26. 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.
27. 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/OL]. Acta Ophthalmol, 2020, 98(6): e730-e733[2020-02-24]. https://pubmed.ncbi.nlm.nih.gov/32096343/. DOI: 10.1111/aos.14379.
28. Zhang Y, Li X, Yuan J, 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.
29. Feuer WJ, Schiffman JC, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: initial results[J]. Ophthalmology, 2016, 123(3): 558-570. DOI: 10.1016/j.ophtha.2015.10.025.
30. Vignal C, Uretsky S, Fitoussi S, et al. Safety of rAAV2/2-ND4 gene therapy for Leber hereditary optic neuropathy[J]. Ophthalmology, 2018, 125(6): 945-947. DOI: 10.1016/j.ophtha.2017.12.036.
31. Vignal-Clermont C, Girmens JF, Audo I, et al. Safety of intravitreal gene therapy for treatment of subjects with Leber hereditary optic neuropathy due to mutations in the mitochondrial ND4 gene: The REVEAL Study[J]. BioDrugs, 2021, 35(2): 201-214. DOI: 10.1007/s40259-021-00468-9.
32. Newman NJ, Yu-Wai-Man P, Carelli V, et al. Efficacy and safety of intravitreal gene therapy for Leber hereditary optic neuropathy treated within 6 months of disease onset[J]. Ophthalmology, 2021, 128(5): 649-660. DOI: 10.1016/j.ophtha.2020.12.012.
33. Yu-Wai-Man P, Newman N J, Carelli V, et al. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy[J/OL]. Sci Transl Med, 2020, 12(573): e7423[2020-12-09]. https://pubmed.ncbi.nlm.nih.gov/33298565/. DOI: 10.1126/scitranslmed.aaz7423.
34. Biousse V, Newman NJ, Yu-Wai-Man P, et al. Long-term follow-up after unilateral intravitreal gene therapy for Leber hereditary optic neuropathy: The RESTORE Study[J]. J Neuroophthalmol, 2021, 41(3): 309-315. DOI: 10.1097/WNO.0000000000001367.
35. 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.
36. Zingg B, Chou XL, Zhang ZG, et al. AAV-mediated anterograde transsynaptic tagging: mapping corticocollicular input-defined neural pathways for defense behaviors[J]. Neuron, 2017, 93(1): 33-47. DOI: 10.1016/j.neuron.2016.11.045.
37. Yang S, Chen C, Yuan JJ, et al. Multilocus mitochondrial mutations do not directly affect the efficacy of gene therapy for Leber hereditary optic neuropathy[J]. J Neuroophthalmol, 2020, 40(1): 22-29. DOI: 10.1097/WNO.0000000000000797.
38. Guy J, Feuer WJ, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: low- and medium-dose visual results[J]. Ophthalmology, 2017, 124(11): 1621-1634. DOI: 10.1016/j.ophtha.2017.05.016.
39. Duncan JL. Understanding ocular inflammation in eyes treated with intravitreal gene therapy[J]. JAMA Ophthalmol, 2019, 137(4): 407. DOI: 10.1001/jamaophthalmol.2018.6902.
40. Yang X, Jiang J, Li Z, et al. Strategies for mitochondrial gene editing[J]. Comput Struct Biotechnol J, 2021, 19: 3319-3329. DOI: 10.1016/j.csbj.2021.06.003.

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