New advances in gene therapy with adenoviral vectors for inherited retinal diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Shen Kejiong ,  Shen Yin

Eye Center of Wuhan People's Hospital, Wuhan 430060, China;

Corresponding author：

Shen Yin, Email: yinshen@whu.edu.cn

Keywords：

Retinal diseases/genetics; Gene therapy; Review; Adeno-associated virus

DOI：

10.3760/cma.j.cn511434-20190705-00214

Video：

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Abstract Full text Figures/Tables Video References Cited by

Adeno-associated viral vector (AAV) is the most important viral tool and has been widely used in gene therapy. Because of its small size, non-enveloped, non-pathogenic and other characteristics, so it is one of the main means to treat hereditary retinal diseases. Aiming at MERTK for retinitis pigmentosa, ND4 for Leber hereditary optic neuropathy or RPE1 for choroideremia, AAV gene therapy improved half patients’ visual acuity in clinic tests. Besides, there are some clinic tests in progress for Leber’s congenital amaurosis, X-linked retinoschisis, Achromatopsia, age-related macular degeneration. But more researches need to be found before clinic test for Stargardt disease, Usher syndrome and nanophthalmos. At present, AAV gene therapy is mainly used for recessive hereditary retinal diseases, and technology is needed to intervene for dominant retinal diseases. For the treatment of hereditary retinal diseases, this will be an important and complex systematic project, which requires more human and material resources to participate in and study together, and we expect to have a great breakthrough in the near future.

Citation： Shen Kejiong, Shen Yin. New advances in gene therapy with adenoviral vectors for inherited retinal diseases. Chinese Journal of Ocular Fundus Diseases, 2020, 36(3): 242-248. doi: 10.3760/cma.j.cn511434-20190705-00214 Copy

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2.	Madigan VJ, Asokan A. Engineering AAV receptor footprints for gene therapy[J]. Curr Opin Virol, 2016, 18: 89-96. DOI: 10.1016/j.coviro.2016.05.001.
3.	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]. Proc Natl Acad Sci USA, 2012, 109(20): 1238-1247. DOI: 10.1073/pnas.1119577109.
4.	Lotery AJ, Yang GS, Mullins RF, et al. Adeno-associated virus type 5: transduction efficiency and cell-type specificity in the primate retina[J]. Hum Gene Ther, 2003, 14(17): 1663-1671. DOI: 10.1089/104303403322542301.
5.	Weber M, Rabinowitz J, Provost N, et al. Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery[J]. Mol Ther, 2003, 7(6): 774-781. DOI: 10.1016/S1525-0016(03)00098-4.
6.	Agbandje-McKenna M, Kleinschmidt J. AAV capsid structure and cell interactions[J]. Methods Mol Biol, 2011, 807: 47-92. DOI: 10.1007/978-1-61779-370-7_3.
7.	Van Vliet KM, Blouin V, Brument N, et al. The role of the adeno-associated virus capsid in gene transfer[J]. Methods Mol Biol, 2008, 437: 51-91. DOI: 10.1007/978-1-59745-210-6_2.
8.	Duong TT, Lim J, Vasireddy V, et al. Comparative AAV-eGFP transgene expression using vector serotypes 1-9, 7m8, and 8b in human pluripotent stem cells, RPEs, and human and rat cortical neurons[J/OL]. Stem Cells Int, 2019, 2019: 7281912[2019-01-17]. https://dx.doi.org/10.1155/2019/7281912. DOI: 10.1155/2019/7281912.
9.	Duong TT, Vasireddy V, Ramachandran P, et al. Use of induced pluripotent stem cell models to probe the pathogenesis of choroideremia and to develop a potential treatment[J]. Stem Cell Res, 2018, 27: 140-150. DOI: 10.1016/j.scr.2018.01.009.
10.	Hughes CP, O' Flynn NMJ, Gatherer M, et al. AAV2/8 anti-angiogenic gene therapy using single-chain antibodies inhibits murine choroidal neovascularization[J]. Mol Ther Methods Clin Dev, 2019, 13: 86-98. DOI: 10.1016/j.omtm.2018.11.005.
11.	Hickey DG, Edwards TL, Barnard AR, et al. Tropism of engineered and evolved recombinant AAV serotypes in the rd1 mouse and ex vivo primate retina[J]. Gene Ther, 2017, 24(12): 787-800. DOI: 10.1038/gt.2017.85.
12.	Guziewicz KE, Zangerl B, Komaromy AM, et al. Recombinant AAV-mediated BEST1 transfer to the retinal pigment epithelium: analysis of serotype-dependent retinal effects[J/OL]. PLoS One, 2013, 8(10): 75666[2013-010-15]. http://dx.plos.org/10.1371/journal.pone.0075666. DOI: 10.1371/journal.pone.0075666.
13.	De Silva SR, Charbel Issa P, Singh MS, et al. Single residue AAV capsid mutation improves transduction of photoreceptors in the Abca4(-/-) mouse and bipolar cells in the rd1 mouse and human retina ex vivo[J]. Gene Ther, 2016, 23(11): 767-774. DOI: 10.1038/gt.2016.54.
14.	Katada Y, Kobayashi K, Tsubota K, et al. Evaluation of AAV-DJ vector for retinal gene therapy[J/OL]. PeerJ, 2019, 7: 6317[2019-01-17]. https://doi.org/10.7717/peerj.6317. DOI: 10.7717/peerj.6317.
15.	Alves CH, Wijnholds J. AAV gene augmentation therapy for CRB1-associated retinitis pigmentosa[J]. Methods Mol Biol, 2018, 1715: 135-151. DOI: 10.1007/978-1-4939-7522-8_10.
16.	Michalakis S, Koch S, Sothilingam V, et al. Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa[J]. Adv Exp Med Biol, 2014, 801: 733-739. DOI: 10.1007/978-1-4614-3209-8_92.
17.	Ghazi NG, Abboud EB, Nowilaty SR, et al. Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase Ⅰ trial[J]. Hum Genet, 2016, 135(3): 327-343. DOI: 10.1007/s00439-016-1637-y.
18.	Moore NA, Morral N, Ciulla TA, et al. Gene therapy for inherited retinal and optic nerve degenerations[J]. Expert Opin Biol Ther, 2018, 18(1): 37-49. DOI: 10.1080/14712598.2018.1389886.
19.	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.
20.	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]. http://dx.doi.org/10.1038/srep21587. DOI: 10.1038/srep21587.
21.	Binley K, Widdowson P, Loader J, et al. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease[J]. Invest Ophthalmol Vis Sci, 2013, 54(6): 4061-4071. DOI: 10.1167/iovs.13-11871.
22.	Trapani I. Dual AAV vectors for Stargardt disease[J]. Methods Mol Biol, 2018, 1715: 153-175. DOI: 10.1007/978-1-4939-7522-8_11.
23.	Dinculescu A, Stupay RM, Deng WT, et al. AAV-mediated clarin-1 expression in the mouse retina: implications for USH3A gene therapy[J/OL]. PLoS One, 2016, 11(2): 0148874[2016-02-16]. http://dx.plos.org/10.1371/journal.pone.0148874. DOI: 10.1371/journal.pone.0148874.
24.	MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial[J]. Lancet, 2014, 383(9923): 1129-1137. DOI: 10.1016/S0140-6736(13)62117-0.
25.	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.
26.	张阳阳, 戴旭锋, 张华, 等. X连锁视网膜劈裂症分子遗传学研究与基因治疗的现状及进展[J]. 中华眼底病杂志, 2016, 32(6): 657-660. DOI: 10.3670/cma.j.issn.1005-1015.2016.06.027.Zhang YY, Dai XF, Zhang H, et al. Molecular genetics and gene therapy of X-linked congenital retinoschisis[J]. Chin J Ocul Fundus Dis, 2016, 32(6): 657-660. DOI: 10.3670/cma.j.issn.1005-1015.2016.06.027.
27.	Askou AL, Alsing S, Benckendorff JNE, et al. Suppression of choroidal neovascularization by AAV-based dual-acting antiangiogenic gene therapy[J]. Mol Ther Nucleic Acids, 2019, 16: 38-50. DOI: 10.1016/j.omtn.2019.01.012.
28.	Lambert NG, Zhang X, Rai RR, et al. Subretinal AAV2.COMP-Ang1 suppresses choroidal neovascularization and vascular endothelial growth factor in a murine model of age-related macular degeneration[J]. Exp Eye Res, 2016, 145: 248-257. DOI: 10.1016/j.exer.2016.01.009.
29.	Zhang X, Das SK, Passi SF, et al. AAV2 delivery of Flt23k intraceptors inhibits murine choroidal neovascularization[J]. Mol Ther, 2015, 23(2): 226-234. DOI: 10.1038/mt.2014.199.
30.	Heier JS, Kherani S, Desai S, et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial[J]. Lancet, 2017, 390(10089): 50-61. DOI: 10.1016/S0140-6736(17)30979-0.
31.	Rakoczy EP, Lai CM, Magno AL, et al. Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial[J]. Lancet, 2015, 386(10011): 2395-2403. DOI: 10.1016/S0140-6736(15)00345-1.
32.	Rakoczy EP, Magno AL, Lai CM, et al. Three-year follow-up of phase 1 and 2a rAAV.sFLT-1 subretinal gene therapy trials for exudative age related macular degeneration[J]. Am J Ophthalmol, 2019, 204: 113-123. DOI: 10.1016/j.ajo.2019.03.006.
33.	Shi H, Zhu R, Hu N, et al. Association of frizzled-related protein (MFRP) and heat shock protein 70 (HSP70) single nucleotide polymorphisms with primary angle closure in a Han Chinese population: Jiangsu Eye Study[J]. Mol Vis, 2013, 19: 128-134.
34.	Collery RF, Volberding PJ, Bostrom JR, et al. Loss of zebrafish MFRP causes nanophthalmia, hyperopia, and accumulation of subretinal macrophages[J]. Invest Ophthalmol Vis Sci, 2016, 57(15): 6805-6814. DOI: 10.1167/iovs.16-19593.
35.	Velez G, Tsang SH, Tsai YT, et al. Gene therapy restores MFRP and corrects axial eye length[J/OL]. Sci Rep, 2017, 7(1): 16151[2017-11-23]. http://dx.doi.org/10.1038/s41598-017-16275-8. DOI: 10.1038/s41598-017-16275-8.
36.	Li Y, Wu WH, Hsu CW, et al. Gene therapy in patient-specific stem cell lines and a preclinical model of retinitis pigmentosa with membrane frizzled-related protein defects[J]. Mol Ther, 2014, 22(9): 1688-1697. DOI: 10.1038/mt.2014.100.
37.	Pillay S, Zou W, Cheng F, et al. AAV serotypes have distinctive interactions with domains of the cellular receptor AAVR[J/OL]. J Virol, 2017, 91(18): e00391-17[2017-08-24]. http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=28679762. DOI: 10.1128/JVI.00391-17.
38.	Berns KI, Muzyczka N. AAV: an overview of unanswered questions[J]. Hum Gene Ther, 2017, 28(4): 308-313. DOI: 10.1089/hum.2017.048.
39.	Grimm D, Buning H. Small but increasingly mighty: latest advances in AAV vector research, design, and evolution[J]. Hum Gene Ther, 2017, 28(11): 1075-1086. DOI: 10.1089/hum.2017.172.
40.	Xiong W, Wu DM, Xue Y, et al. AAV cis-regulatory sequences are correlated with ocular toxicity[J]. Proc Natl Acad Sci USA, 2019, 116(12): 5785-5794. DOI: 10.1073/pnas.1821000116.

1. 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.
2. Madigan VJ, Asokan A. Engineering AAV receptor footprints for gene therapy[J]. Curr Opin Virol, 2016, 18: 89-96. DOI: 10.1016/j.coviro.2016.05.001.
3. 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]. Proc Natl Acad Sci USA, 2012, 109(20): 1238-1247. DOI: 10.1073/pnas.1119577109.
4. Lotery AJ, Yang GS, Mullins RF, et al. Adeno-associated virus type 5: transduction efficiency and cell-type specificity in the primate retina[J]. Hum Gene Ther, 2003, 14(17): 1663-1671. DOI: 10.1089/104303403322542301.
5. Weber M, Rabinowitz J, Provost N, et al. Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery[J]. Mol Ther, 2003, 7(6): 774-781. DOI: 10.1016/S1525-0016(03)00098-4.
6. Agbandje-McKenna M, Kleinschmidt J. AAV capsid structure and cell interactions[J]. Methods Mol Biol, 2011, 807: 47-92. DOI: 10.1007/978-1-61779-370-7_3.
7. Van Vliet KM, Blouin V, Brument N, et al. The role of the adeno-associated virus capsid in gene transfer[J]. Methods Mol Biol, 2008, 437: 51-91. DOI: 10.1007/978-1-59745-210-6_2.
8. Duong TT, Lim J, Vasireddy V, et al. Comparative AAV-eGFP transgene expression using vector serotypes 1-9, 7m8, and 8b in human pluripotent stem cells, RPEs, and human and rat cortical neurons[J/OL]. Stem Cells Int, 2019, 2019: 7281912[2019-01-17]. https://dx.doi.org/10.1155/2019/7281912. DOI: 10.1155/2019/7281912.
9. Duong TT, Vasireddy V, Ramachandran P, et al. Use of induced pluripotent stem cell models to probe the pathogenesis of choroideremia and to develop a potential treatment[J]. Stem Cell Res, 2018, 27: 140-150. DOI: 10.1016/j.scr.2018.01.009.
10. Hughes CP, O' Flynn NMJ, Gatherer M, et al. AAV2/8 anti-angiogenic gene therapy using single-chain antibodies inhibits murine choroidal neovascularization[J]. Mol Ther Methods Clin Dev, 2019, 13: 86-98. DOI: 10.1016/j.omtm.2018.11.005.
11. Hickey DG, Edwards TL, Barnard AR, et al. Tropism of engineered and evolved recombinant AAV serotypes in the rd1 mouse and ex vivo primate retina[J]. Gene Ther, 2017, 24(12): 787-800. DOI: 10.1038/gt.2017.85.
12. Guziewicz KE, Zangerl B, Komaromy AM, et al. Recombinant AAV-mediated BEST1 transfer to the retinal pigment epithelium: analysis of serotype-dependent retinal effects[J/OL]. PLoS One, 2013, 8(10): 75666[2013-010-15]. http://dx.plos.org/10.1371/journal.pone.0075666. DOI: 10.1371/journal.pone.0075666.
13. De Silva SR, Charbel Issa P, Singh MS, et al. Single residue AAV capsid mutation improves transduction of photoreceptors in the Abca4(-/-) mouse and bipolar cells in the rd1 mouse and human retina ex vivo[J]. Gene Ther, 2016, 23(11): 767-774. DOI: 10.1038/gt.2016.54.
14. Katada Y, Kobayashi K, Tsubota K, et al. Evaluation of AAV-DJ vector for retinal gene therapy[J/OL]. PeerJ, 2019, 7: 6317[2019-01-17]. https://doi.org/10.7717/peerj.6317. DOI: 10.7717/peerj.6317.
15. Alves CH, Wijnholds J. AAV gene augmentation therapy for CRB1-associated retinitis pigmentosa[J]. Methods Mol Biol, 2018, 1715: 135-151. DOI: 10.1007/978-1-4939-7522-8_10.
16. Michalakis S, Koch S, Sothilingam V, et al. Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa[J]. Adv Exp Med Biol, 2014, 801: 733-739. DOI: 10.1007/978-1-4614-3209-8_92.
17. Ghazi NG, Abboud EB, Nowilaty SR, et al. Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase Ⅰ trial[J]. Hum Genet, 2016, 135(3): 327-343. DOI: 10.1007/s00439-016-1637-y.
18. Moore NA, Morral N, Ciulla TA, et al. Gene therapy for inherited retinal and optic nerve degenerations[J]. Expert Opin Biol Ther, 2018, 18(1): 37-49. DOI: 10.1080/14712598.2018.1389886.
19. 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.
20. 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]. http://dx.doi.org/10.1038/srep21587. DOI: 10.1038/srep21587.
21. Binley K, Widdowson P, Loader J, et al. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease[J]. Invest Ophthalmol Vis Sci, 2013, 54(6): 4061-4071. DOI: 10.1167/iovs.13-11871.
22. Trapani I. Dual AAV vectors for Stargardt disease[J]. Methods Mol Biol, 2018, 1715: 153-175. DOI: 10.1007/978-1-4939-7522-8_11.
23. Dinculescu A, Stupay RM, Deng WT, et al. AAV-mediated clarin-1 expression in the mouse retina: implications for USH3A gene therapy[J/OL]. PLoS One, 2016, 11(2): 0148874[2016-02-16]. http://dx.plos.org/10.1371/journal.pone.0148874. DOI: 10.1371/journal.pone.0148874.
24. MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial[J]. Lancet, 2014, 383(9923): 1129-1137. DOI: 10.1016/S0140-6736(13)62117-0.
25. 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.
26. 张阳阳, 戴旭锋, 张华, 等. X连锁视网膜劈裂症分子遗传学研究与基因治疗的现状及进展[J]. 中华眼底病杂志, 2016, 32(6): 657-660. DOI: 10.3670/cma.j.issn.1005-1015.2016.06.027.Zhang YY, Dai XF, Zhang H, et al. Molecular genetics and gene therapy of X-linked congenital retinoschisis[J]. Chin J Ocul Fundus Dis, 2016, 32(6): 657-660. DOI: 10.3670/cma.j.issn.1005-1015.2016.06.027.
27. Askou AL, Alsing S, Benckendorff JNE, et al. Suppression of choroidal neovascularization by AAV-based dual-acting antiangiogenic gene therapy[J]. Mol Ther Nucleic Acids, 2019, 16: 38-50. DOI: 10.1016/j.omtn.2019.01.012.
28. Lambert NG, Zhang X, Rai RR, et al. Subretinal AAV2.COMP-Ang1 suppresses choroidal neovascularization and vascular endothelial growth factor in a murine model of age-related macular degeneration[J]. Exp Eye Res, 2016, 145: 248-257. DOI: 10.1016/j.exer.2016.01.009.
29. Zhang X, Das SK, Passi SF, et al. AAV2 delivery of Flt23k intraceptors inhibits murine choroidal neovascularization[J]. Mol Ther, 2015, 23(2): 226-234. DOI: 10.1038/mt.2014.199.
30. Heier JS, Kherani S, Desai S, et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial[J]. Lancet, 2017, 390(10089): 50-61. DOI: 10.1016/S0140-6736(17)30979-0.
31. Rakoczy EP, Lai CM, Magno AL, et al. Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial[J]. Lancet, 2015, 386(10011): 2395-2403. DOI: 10.1016/S0140-6736(15)00345-1.
32. Rakoczy EP, Magno AL, Lai CM, et al. Three-year follow-up of phase 1 and 2a rAAV.sFLT-1 subretinal gene therapy trials for exudative age related macular degeneration[J]. Am J Ophthalmol, 2019, 204: 113-123. DOI: 10.1016/j.ajo.2019.03.006.
33. Shi H, Zhu R, Hu N, et al. Association of frizzled-related protein (MFRP) and heat shock protein 70 (HSP70) single nucleotide polymorphisms with primary angle closure in a Han Chinese population: Jiangsu Eye Study[J]. Mol Vis, 2013, 19: 128-134.
34. Collery RF, Volberding PJ, Bostrom JR, et al. Loss of zebrafish MFRP causes nanophthalmia, hyperopia, and accumulation of subretinal macrophages[J]. Invest Ophthalmol Vis Sci, 2016, 57(15): 6805-6814. DOI: 10.1167/iovs.16-19593.
35. Velez G, Tsang SH, Tsai YT, et al. Gene therapy restores MFRP and corrects axial eye length[J/OL]. Sci Rep, 2017, 7(1): 16151[2017-11-23]. http://dx.doi.org/10.1038/s41598-017-16275-8. DOI: 10.1038/s41598-017-16275-8.
36. Li Y, Wu WH, Hsu CW, et al. Gene therapy in patient-specific stem cell lines and a preclinical model of retinitis pigmentosa with membrane frizzled-related protein defects[J]. Mol Ther, 2014, 22(9): 1688-1697. DOI: 10.1038/mt.2014.100.
37. Pillay S, Zou W, Cheng F, et al. AAV serotypes have distinctive interactions with domains of the cellular receptor AAVR[J/OL]. J Virol, 2017, 91(18): e00391-17[2017-08-24]. http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=28679762. DOI: 10.1128/JVI.00391-17.
38. Berns KI, Muzyczka N. AAV: an overview of unanswered questions[J]. Hum Gene Ther, 2017, 28(4): 308-313. DOI: 10.1089/hum.2017.048.
39. Grimm D, Buning H. Small but increasingly mighty: latest advances in AAV vector research, design, and evolution[J]. Hum Gene Ther, 2017, 28(11): 1075-1086. DOI: 10.1089/hum.2017.172.
40. Xiong W, Wu DM, Xue Y, et al. AAV cis-regulatory sequences are correlated with ocular toxicity[J]. Proc Natl Acad Sci USA, 2019, 116(12): 5785-5794. DOI: 10.1073/pnas.1821000116.

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