The status and progress of gene therapy delivery techniques for retinal diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Liang Licong , She Kaiqin ,  Lu Fang

Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610000, China;

Corresponding author：

Lu Fang, Email: lufang@wshscu.cn

Keywords：

Retinal diseases; Gene therapy; Gene delivery; Subretinal injection; Intravitreal injection; Suprachoroidal injection; Review

DOI：

10.3760/cma.j.cn511434-20220803-00435

Video：

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Gene therapy is designed to introduce genetic material into the cells of a patient via virus to enhance, inhibit, edit or add a genetic sequence, results in a therapeutic or prophylactic effect. Gene therapy has brought positive influence and great potential for the treatment of retinal diseases including genetic retinal diseases and acquired retinal diseases. In addition to the constant optimization of gene vectors, the exploration of different drug delivery techniques has brought different therapeutic effects for gene therapy of retinal diseases. The main delivery methods include subretinal injection, intravitreal injection, suprachoroidal injection. Considering the transfection efficiency and safety of delivery methods, emerging sub-inner limiting membrane injection and noninvasive gene delivery are under investigation. The selection of gene delivery method is very important for the safety and effectiveness of gene therapy for retinal diseases. It is not only related to the development of equipment and technology, but also related to the modification of adeno-associated virus, the selection of promoter and the specific retinal cells that the target gene wants to be transfected. Therefore, the most appropriate method of gene delivery should be selected according to the final gene therapy agent and the specific transfected cells after taking all these factors into consideration.

Citation： Liang Licong, She Kaiqin, Lu Fang. The status and progress of gene therapy delivery techniques for retinal diseases. Chinese Journal of Ocular Fundus Diseases, 2024, 40(1): 67-75. doi: 10.3760/cma.j.cn511434-20220803-00435 Copy

1.	Lee JH, Wang JH, Chen J, et al. Gene therapy for visual loss: opportunities and concerns[J]. Prog Retin Eye Res, 2019, 68: 31-53. DOI: 10.1016/j.preteyeres.2018.08.003.
2.	Kansara V, Muya L, Wan CR, et al. Suprachoroidal delivery of viral and nonviral gene therapy for retinal diseases[J]. J Ocul Pharmacol Ther, 2020, 36(6): 384-392. DOI: 10.1089/jop.2019.0126.
3.	Verbakel SK, Van Huet R, Boon CJF, et al. Non-syndromic retinitis pigmentosa[J]. Prog Retin Eye Res, 2018, 66: 157-186. DOI: 10.1016/j.preteyeres.2018.03.005.
4.	Dias MF, Joo K, Kemp JA, et al. Molecular genetics and emerging therapies for retinitis pigmentosa: basic research and clinical perspectives[J]. Prog Retin Eye Res, 2018, 63: 107-131. DOI: 10.1016/j.preteyeres.2017.10.004.
5.	Giacalone JC, Andorf JL, Zhang Q, et al. Development of a molecularly stable gene therapy vector for the treatment of RPGR-associated X-linked retinitis pigmentosa[J]. Hum Gene Ther, 2019, 30(8): 967-974. DOI: 10.1089/hum.2018.244.
6.	Tobias P, Philipp SI, Stylianos M, et al. Safety and toxicology of ocular gene therapy with recombinant AAV vector rAAV. hCNGA3 in nonhuman primates[J]. Hum Gene Ther Clin Dev, 2019, 30(2): 50-56. DOI: 10.1089/humc.2018.188.
7.	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.
8.	Grishanin R, Vuillemenot B, Sharma P, et al. Preclinical evaluation of ADVM-022, a novel gene therapy approach to treating wet age-related macular degeneration[J]. Mol Ther, 2019, 27(1): 118-129. DOI: 10.1016/j.ymthe.2018.11.003.
9.	Hartman RR, Kompella UB. Intravitreal, subretinal, and suprachoroidal injections: evolution of microneedles for drug delivery[J]. J Ocul Pharmacol Ther, 2018, 34(1-2): 141-153. DOI: 10.1089/jop.2017.0121.
10.	Xue K, Groppe M, Salvetti AP, et al. Technique of retinal gene therapy: delivery of viral vector into the subretinal space[J]. Eye (Lond), 2017, 31(9): 1308-1316. DOI: 10.1038/eye.2017.158.
11.	Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, et al. Current clinical applications of in vivo gene therapy with AAVs[J]. Mol Ther, 2021, 29(2): 464-488. DOI: 10.1016/j.ymthe.2020.12.007.
12.	Kashani AH, Uang J, Mert M, et al. Surgical method for implantation of a biosynthetic retinal pigment epithelium monolayer for geographic atrophy: experience from a phase 1/2a study[J]. Ophthalmol Retina, 2020, 4(3): 264-273. DOI: 10.1016/j.oret.2019.09.017.
13.	Yiu G, Chung SH, Mollhoff IN, et al. Suprachoroidal and subretinal injections of AAV using transscleral microneedles for retinal gene delivery in nonhuman primates[J]. Mol Ther Methods Clin Dev, 2020, 16: 179-191. DOI: 10.1016/j.omtm.2020.01.002.
14.	Davis JL, Gregori NZ, Maclaren RE, et al. Surgical technique for subretinal gene therapy in humans with inherited retinal degeneration[J]. Retina, 2019, 39(Suppl 1): S2-8. DOI: 10.1097/iae.0000000000002609.
15.	Gregori NZ, Lam BL, Davis JL. Intraoperative use of microscope-integrated optical coherence tomography for subretinal gene therapy delivery[J]. Retina, 2019, 39(Suppl 1): S9-12. DOI: 10.1097/iae.0000000000001646.
16.	Scruggs BA, Jiao C, Cranston CM, et al. Optimizing donor cellular dissociation and subretinal injection parameters for stem cell-based treatments[J]. Stem Cells Transl Med, 2019, 8(8): 797-809. DOI: 10.1002/sctm.18-0210.
17.	Takahashi K, Morizane Y, Hisatomi T, et al. The influence of subretinal injection pressure on the microstructure of the monkey retina[J/OL]. PLoS One, 2018, 13(12): e0209996[2018-12-31]. https://pubmed.ncbi.nlm.nih.gov/30596769/. DOI: 10.1371/journal.pone.0209996.
18.	Weed L, Ammar MJ, Zhou S, et al. Safety of same-eye subretinal sequential readministration of AAV2-hRPE65v2 in non-human primates[J]. Mol Ther Methods Clin Dev, 2019, 15: 133-148. DOI: 10.1016/j.omtm.2019.08.011.
19.	Frederick A, Sullivan J, Liu L, et al. Engineered capsids for efficient gene delivery to the retina and cornea[J]. Hum Gene Ther, 2020, 31(13-14): 756-774. DOI: 10.1089/hum.2020.070.
20.	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.
21.	Weleber RG, Pennesi ME, Wilson DJ, et al. Results at 2 years after gene therapy for RPE65-deficient leber congenital amaurosis and severe early-childhood-onset retinal dystrophy[J]. Ophthalmology, 2016, 123(7): 1606-1620. DOI: 10.1016/j.ophtha.2016.03.003.
22.	Georgiadis A, Duran Y, Ribeiro J, et al. Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65[J]. Gene Ther, 2016, 23(12): 857-862. DOI: 10.1038/gt.2016.66.
23.	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.
24.	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.
25.	Dimopoulos IS, Hoang SC, Radziwon A, et al. Two-year results after AAV2-mediated gene therapy for choroideremia: the alberta experience[J]. Am J Ophthalmol, 2018, 193: 130-142. DOI: 10.1016/j.ajo.2018.06.011.
26.	Lam BL, Davis JL, Gregori NZ, et al. Choroideremia gene therapy phase 2 clinical trial: 24-month results[J]. Am J Ophthalmol, 2019, 197: 65-73. DOI: 10.1016/j.ajo.2018.09.012.
27.	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.
28.	Jiang DJ, Xu CL, Tsang SH. Revolution in gene medicine therapy and genome surgery[J]. Genes (Basel), 2018, 9(12): 575. DOI: 10.3390/genes9120575.
29.	Zallocchi M, Binley K, Lad Y, et al. EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: development of UshStat[J/OL]. PLoS One, 2014, 9(4): e94272[2014-04-04]. https://pubmed.ncbi.nlm.nih.gov/24705452/. DOI: 10.1371/journal.pone.0094272.
30.	Kahle NA, Peters T, Zobor D, et al. Development of methodology and study protocol: safety and efficacy of a single subretinal injection of rAAV. hCNGA3 in patients with CNGA3-linked achromatopsia investigated in an exploratory dose-escalation trial[J]. Hum Gene Ther Clin Dev, 2018, 29(3): 121-131. DOI: 10.1089/humc.2018.088.
31.	Song C, Conlon TJ, Deng WT, et al. Toxicology and pharmacology of an AAV vector expressing codon-optimized RPGR in RPGR-deficient Rd9 mice[J]. Hum Gene Ther Clin Dev, 2018, 29(4): 188-197. DOI: 10.1089/humc.2018.168.
32.	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.
33.	Choi VW, Bigelow CE, Mcgee TL, et al. AAV-mediated RLBP1 gene therapy improves the rate of dark adaptation in Rlbp1 knockout mice[J/OL]. Mol Ther Methods Clin Dev, 2015, 2: 15022[2015-07-08]. https://pubmed.ncbi.nlm.nih.gov/26199951/. DOI: 10.1038/mtm.2015.22.
34.	Min SH, Molday LL, Seeliger MW, et al. Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of X-linked juvenile retinoschisis[J]. Mol Ther, 2005, 12(4): 644-651. DOI: 10.1016/j.ymthe.2005.06.002.
35.	Mishra A, Sieving PA. X-linked retinoschisis and gene therapy[J]. Int Ophthalmol Clin, 2021, 61(4): 173-184. DOI: 10.1097/iio.0000000000000373.
36.	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.
37.	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.
38.	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.
39.	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.
40.	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.
41.	Busbee B, Boyer DS, Khanani AM, et al. Phase 1 study of intravitreal gene therapy with ADVM-022 for neovascular AMD (OPTIC Trial)[J]. Invest Ophthalmol Vis Sci, 2021, 62(8): 352-352.
42.	Kiss S, Oresic Bender K, Grishanin RN, et al. Long-term safety evaluation of continuous intraocular delivery of Aflibercept by the intravitreal gene therapy candidate ADVM-022 in nonhuman primates[J]. Transl Vis Sci Technol, 2021, 10(1): 34. DOI: 10.1167/tvst.10.1.34.
43.	Cwerman-Thibault H, Augustin S, Lechauve C, et al. Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss[J/OL]. Mol Ther Methods Clin Dev, 2015, 2: 15003[2015-02-25]. https://pubmed.ncbi.nlm.nih.gov/26029714/. DOI: 10.1038/mtm.2015.3.
44.	Kampougeris G, Spyropoulos D, Mitropoulou A. Intraocular pressure rise after anti-VEGF treatment: prevalence, possible mechanisms and correlations[J]. J Curr Glaucoma Pract, 2013, 7(1): 19-24. DOI: 10.5005/jp-journals-10008-1132.
45.	Dalkara D, Byrne LC, Klimczak RR, et al. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous[J]. Sci Transl Med, 2013, 5(189): 11. DOI: 10.1126/scitranslmed.3005708.
46.	Bashar AE, Metcalfe AL, Viringipurampeer IA, et al. An ex vivo gene therapy approach in X-linked retinoschisis[J]. Molecular Vision, 2016, 22: 718-733.
47.	Fischer MD, Huber G, Beck SC, et al. Noninvasive, in vivo assessment of mouse retinal structure using optical coherence tomography[J/OL]. PLoS One, 2009, 4(10): e7507[2009-10-19]. https://pubmed.ncbi.nlm.nih.gov/19838301/. DOI: 10.1371/journal.pone.0007507.
48.	Zhang Y, Bazzazi H, Lima ESR, et al. Three-dimensional transport model for intravitreal and suprachoroidal drug injection[J]. Invest Ophthalmol Vis Sci, 2018, 59(12): 5266-5276. DOI: 10.1167/iovs.17-23632.
49.	Chung SH, Mollhoff IN, Mishra A, et al. Host immune responses after suprachoroidal delivery of AAV8 in nonhuman primate eyes[J]. Hum Gene Ther, 2021, 32(13-14): 682-693. DOI: 10.1089/hum.2020.281.
50.	Kotterman MA, Yin L, Strazzeri JM, et al. Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates[J]. Gene Ther, 2015, 22(2): 116-126. DOI: 10.1038/gt.2014.115.
51.	Xu D, Khan MA, Ho AC. Creating an ocular biofactory: surgical approaches in gene therapy for acquired retinal diseases[J]. Asia Pac J Ophthalmol (Phila), 2021, 10(1): 5-11. DOI: 10.1097/apo.0000000000000362.
52.	Seitz IP, Michalakis S, Wilhelm B, et al. Superior retinal gene transfer and biodistribution profile of subretinal versus intravitreal delivery of AAV8 in nonhuman primates[J]. Invest Ophthalmol Vis Sci, 2017, 58(13): 5792-5801. DOI: 10.1167/iovs.17-22473.
53.	Byrne LC, Day TP, Visel M, et al. In vivo-directed evolution of adeno-associated virus in the primate retina[J/OL]. JCI Insight, 2020, 5(10): e135112[2020-05-21]. https://pubmed.ncbi.nlm.nih.gov/32271719/. DOI: 10.1172/jci.insight.135112.
54.	Pavlou M, Schön C, Occelli LM, et al. Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders[J/OL]. EMBO Mol Med, 2021, 13(4): e13392[2021-04-09]. https://pubmed.ncbi.nlm.nih.gov/33616280/. DOI: 10.15252/emmm.202013392.
55.	Petrs-Silva H, Dinculescu A, Li Q, et al. High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors[J]. Mol Ther, 2009, 17(3): 463-471. DOI: 10.1038/mt.2008.269.
56.	Dalkara D, Kolstad KD, Caporale N, et al. Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous[J]. Mol Ther, 2009, 17(12): 2096-2102. DOI: 10.1038/mt.2009.181.
57.	Takahashi K, Igarashi T, Miyake K, et al. Improved intravitreal AAV-mediated inner retinal gene transduction after surgical internal limiting membrane peeling in cynomolgus monkeys[J]. Mol Ther, 2017, 25(1): 296-302. DOI: 10.1016/j.ymthe.2016.10.008.
58.	Calcedo R, Morizono H, Wang L, et al. Adeno-associated virus antibody profiles in newborns, children, and adolescents[J]. Clin Vaccine Immunol, 2011, 18(9): 1586-1588. DOI: 10.1128/cvi.05107-11.
59.	Mével M, Bouzelha M, Leray A, et al. Chemical modification of the adeno-associated virus capsid to improve gene delivery[J]. Chem Sci, 2019, 11(4): 1122-1131. DOI: 10.1039/c9sc04189c.
60.	Marangoni D, Wu ZJ, Wiley HE, et al. Preclinical safety evaluation of a recombinant AAV8 vctor for X-linked retinoschisis after intravitreal administration in rabbits[J]. Hum Gene Ther Clin Dev, 2014, 25(4): 202-211. DOI: 10.1089/humc.2014.067.
61.	Marangoni D, Bush RA, Zeng Y, et al. Ocular and systemic safety of a recombinant AAV8 vector for X-linked retinoschisis gene therapy: GLP studies in rabbits and Rs1-KO mice[J/OL]. Mol Ther Methods Clin Dev, 2016, 5: 16011[2016-03-16]. https://pubmed.ncbi.nlm.nih.gov/27626041/. DOI: 10.1038/mtm.2016.11.
62.	Ye GJ, Conlon T, Erger K, et al. Safety and biodistribution evaluation of rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus vector expressing retinoschisin, in RS1-deficient mice[J]. Hum Gene Ther Clin Dev, 2015, 26(3): 177-184. DOI: 10.1089/humc.2015.077.
63.	Pennesi ME, Yang P, Birch DG, et al. Intravitreal delivery of rAAV2tYF-CB-hRS1 vector for gene augmentation therapy in patients with X-linked retinoschisis: 1-year clinical results[J]. Ophthalmol Retina, 2022, 6(12): 1130-1144. DOI: 10.1016/j.oret.2022.06.013.
64.	Yeh S, Khurana RN, Shah M, et al. Efficacy and safety of suprachoroidal CLS-TA for macular edema secondary to noninfectious uveitis: phase 3 randomized trial[J]. Ophthalmology, 2020, 127(7): 948-955. DOI: 10.1016/j.ophtha.2020.01.006.
65.	Patel SR, Berezovsky DE, Mccarey BE, et al. Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye[J]. Invest Ophthalmol Vis Sci, 2012, 53(8): 4433-4441. DOI: 10.1167/iovs.12-9872.
66.	De Smet MD, Lynch JL, Dejneka NS, et al. A subretinal cell delivery method via suprachoroidal access in minipigs: safety and surgical outcomes[J]. Invest Ophthalmol Vis Sci, 2018, 59(1): 311-320. DOI: 10.1167/iovs.17-22233.
67.	Wan CR, Muya L, Kansara V, et al. Suprachoroidal delivery of small molecules, nanoparticles, gene and cell therapies for ocular diseases[J]. Pharmaceutics, 2021, 13(2): 288. DOI: 10.3390/pharmaceutics13020288.
68.	Han IC, Cheng JL, Burnight ER, et al. Retinal tropism and transduction of adeno-associated virus varies by serotype and route of delivery (intravitreal, subretinal, or suprachoroidal) in rats[J]. Hum Gene Ther, 2020, 31(23-24): 1288-1299. DOI: 10.1089/hum.2020.043.
69.	Ding K, Shen J, Hafiz Z, et al. AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression[J]. J Clin Invest, 2019, 129(11): 4901-4911. DOI: 10.1172/jci129085.
70.	Sarin H. Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability[J]. J Angiogenes Res, 2010, 2: 14. DOI: 10.1186/2040-2384-2-14.
71.	Jung JH, Park S, Chae JJ, et al. Collagenase injection into the suprachoroidal space of the eye to expand drug delivery coverage and increase posterior drug targeting[J/OL]. Exp Eye Res, 2019, 189: 107824[2019-10-01]. https://pubmed.ncbi.nlm.nih.gov/31585119/. DOI: 10.1016/j.exer.2019.107824.
72.	Emami-Naeini P, Yiu G. Medical and surgical applications for the suprachoroidal space[J]. Int Ophthalmol Clin, 2019, 59(1): 195-207. DOI: 10.1097/iio.0000000000000251.
73.	Mellen PL, Heier JS, Gene therapy for neovascular macular degeneration, diabetic retinopathy, and diabetic macular edema[J]. Int Ophthalmol Clin, 2021, 61(4): 229-239. DOI: 10.1097/iio.0000000000000382.
74.	Wasnik VB, Thool AR. Ocular gene therapy: a literature review with focus on current clinical trials[J/OL]. Cureus, 2022, 14(9): e29533[2022-09-24]. https://pubmed.ncbi.nlm.nih.gov/36312652/. DOI: 10.7759/cureus.29533.
75.	Boye SE, Alexander JJ, Witherspoon CD, et al. Highly efficient delivery of adeno-associated viral vectors to the primate retina[J]. Hum Gene Ther, 2016, 27(8): 580-597. DOI: 10.1089/hum.2016.085.
76.	Gamlin PD, Alexander JJ, Boye SL, et al. SubILM injection of AAV for gene delivery to the retina[J]. Methods Mol Biol, 2019, 1950: 249-262. DOI: 10.1007/978-1-4939-9139-6_14.
77.	Patel LN, Zaro JL, Shen WC. Cell penetrating peptides: intracellular pathways and pharmaceutical perspectives[J]. Pharm Res, 2007, 24(11): 1977-1992. DOI: 10.1007/s11095-007-9303-7.
78.	Liu C, Tai L, Zhang W, et al. Penetratin, a potentially powerful absorption enhancer for noninvasive intraocular drug delivery[J]. Mol Pharm, 2014, 11(4): 1218-1227. DOI: 10.1021/mp400681n.
79.	Jiang K, Hu Y, Gao X, et al. Octopus-like flexible vector for noninvasive intraocular delivery of short interfering nucleic acids[J]. Nano Lett, 2019, 19(9): 6410-6417. DOI: 10.1021/acs.nanolett.9b02596.
80.	Liu X, Wu J, Yammine M, et al. Structurally flexible triethanolamine core PAMAM dendrimers are effective nanovectors for DNA transfection in vitro and in vivo to the mouse thymus[J]. Bioconjug Chem, 2011, 22(12): 2461-2473. DOI: 10.1021/bc200275g.
81.	Barar J, Javadzadeh AR, Omidi Y. Ocular novel drug delivery: impacts of membranes and barriers[J]. Expert Opin Drug Deliv, 2008, 5(5): 567-581. DOI: 10.1517/17425247.5.5.567.
82.	Liu C, Jiang K, Tai L, et al. Facile noninvasive retinal gene delivery enabled by penetratin[J]. ACS Appl Mater Interfaces, 2016, 8(30): 19256-19267. DOI: 10.1021/acsami.6b04551.
83.	Tai L, Liu C, Jiang K, et al. A novel penetratin-modified complex for noninvasive intraocular delivery of antisense oligonucleotides[J]. Int J Pharm, 2017, 529(1-2): 347-356. DOI: 10.1016/j.ijpharm.2017.06.090.

1. Lee JH, Wang JH, Chen J, et al. Gene therapy for visual loss: opportunities and concerns[J]. Prog Retin Eye Res, 2019, 68: 31-53. DOI: 10.1016/j.preteyeres.2018.08.003.
2. Kansara V, Muya L, Wan CR, et al. Suprachoroidal delivery of viral and nonviral gene therapy for retinal diseases[J]. J Ocul Pharmacol Ther, 2020, 36(6): 384-392. DOI: 10.1089/jop.2019.0126.
3. Verbakel SK, Van Huet R, Boon CJF, et al. Non-syndromic retinitis pigmentosa[J]. Prog Retin Eye Res, 2018, 66: 157-186. DOI: 10.1016/j.preteyeres.2018.03.005.
4. Dias MF, Joo K, Kemp JA, et al. Molecular genetics and emerging therapies for retinitis pigmentosa: basic research and clinical perspectives[J]. Prog Retin Eye Res, 2018, 63: 107-131. DOI: 10.1016/j.preteyeres.2017.10.004.
5. Giacalone JC, Andorf JL, Zhang Q, et al. Development of a molecularly stable gene therapy vector for the treatment of RPGR-associated X-linked retinitis pigmentosa[J]. Hum Gene Ther, 2019, 30(8): 967-974. DOI: 10.1089/hum.2018.244.
6. Tobias P, Philipp SI, Stylianos M, et al. Safety and toxicology of ocular gene therapy with recombinant AAV vector rAAV. hCNGA3 in nonhuman primates[J]. Hum Gene Ther Clin Dev, 2019, 30(2): 50-56. DOI: 10.1089/humc.2018.188.
7. 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.
8. Grishanin R, Vuillemenot B, Sharma P, et al. Preclinical evaluation of ADVM-022, a novel gene therapy approach to treating wet age-related macular degeneration[J]. Mol Ther, 2019, 27(1): 118-129. DOI: 10.1016/j.ymthe.2018.11.003.
9. Hartman RR, Kompella UB. Intravitreal, subretinal, and suprachoroidal injections: evolution of microneedles for drug delivery[J]. J Ocul Pharmacol Ther, 2018, 34(1-2): 141-153. DOI: 10.1089/jop.2017.0121.
10. Xue K, Groppe M, Salvetti AP, et al. Technique of retinal gene therapy: delivery of viral vector into the subretinal space[J]. Eye (Lond), 2017, 31(9): 1308-1316. DOI: 10.1038/eye.2017.158.
11. Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, et al. Current clinical applications of in vivo gene therapy with AAVs[J]. Mol Ther, 2021, 29(2): 464-488. DOI: 10.1016/j.ymthe.2020.12.007.
12. Kashani AH, Uang J, Mert M, et al. Surgical method for implantation of a biosynthetic retinal pigment epithelium monolayer for geographic atrophy: experience from a phase 1/2a study[J]. Ophthalmol Retina, 2020, 4(3): 264-273. DOI: 10.1016/j.oret.2019.09.017.
13. Yiu G, Chung SH, Mollhoff IN, et al. Suprachoroidal and subretinal injections of AAV using transscleral microneedles for retinal gene delivery in nonhuman primates[J]. Mol Ther Methods Clin Dev, 2020, 16: 179-191. DOI: 10.1016/j.omtm.2020.01.002.
14. Davis JL, Gregori NZ, Maclaren RE, et al. Surgical technique for subretinal gene therapy in humans with inherited retinal degeneration[J]. Retina, 2019, 39(Suppl 1): S2-8. DOI: 10.1097/iae.0000000000002609.
15. Gregori NZ, Lam BL, Davis JL. Intraoperative use of microscope-integrated optical coherence tomography for subretinal gene therapy delivery[J]. Retina, 2019, 39(Suppl 1): S9-12. DOI: 10.1097/iae.0000000000001646.
16. Scruggs BA, Jiao C, Cranston CM, et al. Optimizing donor cellular dissociation and subretinal injection parameters for stem cell-based treatments[J]. Stem Cells Transl Med, 2019, 8(8): 797-809. DOI: 10.1002/sctm.18-0210.
17. Takahashi K, Morizane Y, Hisatomi T, et al. The influence of subretinal injection pressure on the microstructure of the monkey retina[J/OL]. PLoS One, 2018, 13(12): e0209996[2018-12-31]. https://pubmed.ncbi.nlm.nih.gov/30596769/. DOI: 10.1371/journal.pone.0209996.
18. Weed L, Ammar MJ, Zhou S, et al. Safety of same-eye subretinal sequential readministration of AAV2-hRPE65v2 in non-human primates[J]. Mol Ther Methods Clin Dev, 2019, 15: 133-148. DOI: 10.1016/j.omtm.2019.08.011.
19. Frederick A, Sullivan J, Liu L, et al. Engineered capsids for efficient gene delivery to the retina and cornea[J]. Hum Gene Ther, 2020, 31(13-14): 756-774. DOI: 10.1089/hum.2020.070.
20. 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.
21. Weleber RG, Pennesi ME, Wilson DJ, et al. Results at 2 years after gene therapy for RPE65-deficient leber congenital amaurosis and severe early-childhood-onset retinal dystrophy[J]. Ophthalmology, 2016, 123(7): 1606-1620. DOI: 10.1016/j.ophtha.2016.03.003.
22. Georgiadis A, Duran Y, Ribeiro J, et al. Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65[J]. Gene Ther, 2016, 23(12): 857-862. DOI: 10.1038/gt.2016.66.
23. 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.
24. 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.
25. Dimopoulos IS, Hoang SC, Radziwon A, et al. Two-year results after AAV2-mediated gene therapy for choroideremia: the alberta experience[J]. Am J Ophthalmol, 2018, 193: 130-142. DOI: 10.1016/j.ajo.2018.06.011.
26. Lam BL, Davis JL, Gregori NZ, et al. Choroideremia gene therapy phase 2 clinical trial: 24-month results[J]. Am J Ophthalmol, 2019, 197: 65-73. DOI: 10.1016/j.ajo.2018.09.012.
27. 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.
28. Jiang DJ, Xu CL, Tsang SH. Revolution in gene medicine therapy and genome surgery[J]. Genes (Basel), 2018, 9(12): 575. DOI: 10.3390/genes9120575.
29. Zallocchi M, Binley K, Lad Y, et al. EIAV-based retinal gene therapy in the shaker1 mouse model for usher syndrome type 1B: development of UshStat[J/OL]. PLoS One, 2014, 9(4): e94272[2014-04-04]. https://pubmed.ncbi.nlm.nih.gov/24705452/. DOI: 10.1371/journal.pone.0094272.
30. Kahle NA, Peters T, Zobor D, et al. Development of methodology and study protocol: safety and efficacy of a single subretinal injection of rAAV. hCNGA3 in patients with CNGA3-linked achromatopsia investigated in an exploratory dose-escalation trial[J]. Hum Gene Ther Clin Dev, 2018, 29(3): 121-131. DOI: 10.1089/humc.2018.088.
31. Song C, Conlon TJ, Deng WT, et al. Toxicology and pharmacology of an AAV vector expressing codon-optimized RPGR in RPGR-deficient Rd9 mice[J]. Hum Gene Ther Clin Dev, 2018, 29(4): 188-197. DOI: 10.1089/humc.2018.168.
32. 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.
33. Choi VW, Bigelow CE, Mcgee TL, et al. AAV-mediated RLBP1 gene therapy improves the rate of dark adaptation in Rlbp1 knockout mice[J/OL]. Mol Ther Methods Clin Dev, 2015, 2: 15022[2015-07-08]. https://pubmed.ncbi.nlm.nih.gov/26199951/. DOI: 10.1038/mtm.2015.22.
34. Min SH, Molday LL, Seeliger MW, et al. Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of X-linked juvenile retinoschisis[J]. Mol Ther, 2005, 12(4): 644-651. DOI: 10.1016/j.ymthe.2005.06.002.
35. Mishra A, Sieving PA. X-linked retinoschisis and gene therapy[J]. Int Ophthalmol Clin, 2021, 61(4): 173-184. DOI: 10.1097/iio.0000000000000373.
36. 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.
37. 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.
38. 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.
39. 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.
40. 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.
41. Busbee B, Boyer DS, Khanani AM, et al. Phase 1 study of intravitreal gene therapy with ADVM-022 for neovascular AMD (OPTIC Trial)[J]. Invest Ophthalmol Vis Sci, 2021, 62(8): 352-352.
42. Kiss S, Oresic Bender K, Grishanin RN, et al. Long-term safety evaluation of continuous intraocular delivery of Aflibercept by the intravitreal gene therapy candidate ADVM-022 in nonhuman primates[J]. Transl Vis Sci Technol, 2021, 10(1): 34. DOI: 10.1167/tvst.10.1.34.
43. Cwerman-Thibault H, Augustin S, Lechauve C, et al. Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss[J/OL]. Mol Ther Methods Clin Dev, 2015, 2: 15003[2015-02-25]. https://pubmed.ncbi.nlm.nih.gov/26029714/. DOI: 10.1038/mtm.2015.3.
44. Kampougeris G, Spyropoulos D, Mitropoulou A. Intraocular pressure rise after anti-VEGF treatment: prevalence, possible mechanisms and correlations[J]. J Curr Glaucoma Pract, 2013, 7(1): 19-24. DOI: 10.5005/jp-journals-10008-1132.
45. Dalkara D, Byrne LC, Klimczak RR, et al. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous[J]. Sci Transl Med, 2013, 5(189): 11. DOI: 10.1126/scitranslmed.3005708.
46. Bashar AE, Metcalfe AL, Viringipurampeer IA, et al. An ex vivo gene therapy approach in X-linked retinoschisis[J]. Molecular Vision, 2016, 22: 718-733.
47. Fischer MD, Huber G, Beck SC, et al. Noninvasive, in vivo assessment of mouse retinal structure using optical coherence tomography[J/OL]. PLoS One, 2009, 4(10): e7507[2009-10-19]. https://pubmed.ncbi.nlm.nih.gov/19838301/. DOI: 10.1371/journal.pone.0007507.
48. Zhang Y, Bazzazi H, Lima ESR, et al. Three-dimensional transport model for intravitreal and suprachoroidal drug injection[J]. Invest Ophthalmol Vis Sci, 2018, 59(12): 5266-5276. DOI: 10.1167/iovs.17-23632.
49. Chung SH, Mollhoff IN, Mishra A, et al. Host immune responses after suprachoroidal delivery of AAV8 in nonhuman primate eyes[J]. Hum Gene Ther, 2021, 32(13-14): 682-693. DOI: 10.1089/hum.2020.281.
50. Kotterman MA, Yin L, Strazzeri JM, et al. Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates[J]. Gene Ther, 2015, 22(2): 116-126. DOI: 10.1038/gt.2014.115.
51. Xu D, Khan MA, Ho AC. Creating an ocular biofactory: surgical approaches in gene therapy for acquired retinal diseases[J]. Asia Pac J Ophthalmol (Phila), 2021, 10(1): 5-11. DOI: 10.1097/apo.0000000000000362.
52. Seitz IP, Michalakis S, Wilhelm B, et al. Superior retinal gene transfer and biodistribution profile of subretinal versus intravitreal delivery of AAV8 in nonhuman primates[J]. Invest Ophthalmol Vis Sci, 2017, 58(13): 5792-5801. DOI: 10.1167/iovs.17-22473.
53. Byrne LC, Day TP, Visel M, et al. In vivo-directed evolution of adeno-associated virus in the primate retina[J/OL]. JCI Insight, 2020, 5(10): e135112[2020-05-21]. https://pubmed.ncbi.nlm.nih.gov/32271719/. DOI: 10.1172/jci.insight.135112.
54. Pavlou M, Schön C, Occelli LM, et al. Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders[J/OL]. EMBO Mol Med, 2021, 13(4): e13392[2021-04-09]. https://pubmed.ncbi.nlm.nih.gov/33616280/. DOI: 10.15252/emmm.202013392.
55. Petrs-Silva H, Dinculescu A, Li Q, et al. High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors[J]. Mol Ther, 2009, 17(3): 463-471. DOI: 10.1038/mt.2008.269.
56. Dalkara D, Kolstad KD, Caporale N, et al. Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous[J]. Mol Ther, 2009, 17(12): 2096-2102. DOI: 10.1038/mt.2009.181.
57. Takahashi K, Igarashi T, Miyake K, et al. Improved intravitreal AAV-mediated inner retinal gene transduction after surgical internal limiting membrane peeling in cynomolgus monkeys[J]. Mol Ther, 2017, 25(1): 296-302. DOI: 10.1016/j.ymthe.2016.10.008.
58. Calcedo R, Morizono H, Wang L, et al. Adeno-associated virus antibody profiles in newborns, children, and adolescents[J]. Clin Vaccine Immunol, 2011, 18(9): 1586-1588. DOI: 10.1128/cvi.05107-11.
59. Mével M, Bouzelha M, Leray A, et al. Chemical modification of the adeno-associated virus capsid to improve gene delivery[J]. Chem Sci, 2019, 11(4): 1122-1131. DOI: 10.1039/c9sc04189c.
60. Marangoni D, Wu ZJ, Wiley HE, et al. Preclinical safety evaluation of a recombinant AAV8 vctor for X-linked retinoschisis after intravitreal administration in rabbits[J]. Hum Gene Ther Clin Dev, 2014, 25(4): 202-211. DOI: 10.1089/humc.2014.067.
61. Marangoni D, Bush RA, Zeng Y, et al. Ocular and systemic safety of a recombinant AAV8 vector for X-linked retinoschisis gene therapy: GLP studies in rabbits and Rs1-KO mice[J/OL]. Mol Ther Methods Clin Dev, 2016, 5: 16011[2016-03-16]. https://pubmed.ncbi.nlm.nih.gov/27626041/. DOI: 10.1038/mtm.2016.11.
62. Ye GJ, Conlon T, Erger K, et al. Safety and biodistribution evaluation of rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus vector expressing retinoschisin, in RS1-deficient mice[J]. Hum Gene Ther Clin Dev, 2015, 26(3): 177-184. DOI: 10.1089/humc.2015.077.
63. Pennesi ME, Yang P, Birch DG, et al. Intravitreal delivery of rAAV2tYF-CB-hRS1 vector for gene augmentation therapy in patients with X-linked retinoschisis: 1-year clinical results[J]. Ophthalmol Retina, 2022, 6(12): 1130-1144. DOI: 10.1016/j.oret.2022.06.013.
64. Yeh S, Khurana RN, Shah M, et al. Efficacy and safety of suprachoroidal CLS-TA for macular edema secondary to noninfectious uveitis: phase 3 randomized trial[J]. Ophthalmology, 2020, 127(7): 948-955. DOI: 10.1016/j.ophtha.2020.01.006.
65. Patel SR, Berezovsky DE, Mccarey BE, et al. Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye[J]. Invest Ophthalmol Vis Sci, 2012, 53(8): 4433-4441. DOI: 10.1167/iovs.12-9872.
66. De Smet MD, Lynch JL, Dejneka NS, et al. A subretinal cell delivery method via suprachoroidal access in minipigs: safety and surgical outcomes[J]. Invest Ophthalmol Vis Sci, 2018, 59(1): 311-320. DOI: 10.1167/iovs.17-22233.
67. Wan CR, Muya L, Kansara V, et al. Suprachoroidal delivery of small molecules, nanoparticles, gene and cell therapies for ocular diseases[J]. Pharmaceutics, 2021, 13(2): 288. DOI: 10.3390/pharmaceutics13020288.
68. Han IC, Cheng JL, Burnight ER, et al. Retinal tropism and transduction of adeno-associated virus varies by serotype and route of delivery (intravitreal, subretinal, or suprachoroidal) in rats[J]. Hum Gene Ther, 2020, 31(23-24): 1288-1299. DOI: 10.1089/hum.2020.043.
69. Ding K, Shen J, Hafiz Z, et al. AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression[J]. J Clin Invest, 2019, 129(11): 4901-4911. DOI: 10.1172/jci129085.
70. Sarin H. Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability[J]. J Angiogenes Res, 2010, 2: 14. DOI: 10.1186/2040-2384-2-14.
71. Jung JH, Park S, Chae JJ, et al. Collagenase injection into the suprachoroidal space of the eye to expand drug delivery coverage and increase posterior drug targeting[J/OL]. Exp Eye Res, 2019, 189: 107824[2019-10-01]. https://pubmed.ncbi.nlm.nih.gov/31585119/. DOI: 10.1016/j.exer.2019.107824.
72. Emami-Naeini P, Yiu G. Medical and surgical applications for the suprachoroidal space[J]. Int Ophthalmol Clin, 2019, 59(1): 195-207. DOI: 10.1097/iio.0000000000000251.
73. Mellen PL, Heier JS, Gene therapy for neovascular macular degeneration, diabetic retinopathy, and diabetic macular edema[J]. Int Ophthalmol Clin, 2021, 61(4): 229-239. DOI: 10.1097/iio.0000000000000382.
74. Wasnik VB, Thool AR. Ocular gene therapy: a literature review with focus on current clinical trials[J/OL]. Cureus, 2022, 14(9): e29533[2022-09-24]. https://pubmed.ncbi.nlm.nih.gov/36312652/. DOI: 10.7759/cureus.29533.
75. Boye SE, Alexander JJ, Witherspoon CD, et al. Highly efficient delivery of adeno-associated viral vectors to the primate retina[J]. Hum Gene Ther, 2016, 27(8): 580-597. DOI: 10.1089/hum.2016.085.
76. Gamlin PD, Alexander JJ, Boye SL, et al. SubILM injection of AAV for gene delivery to the retina[J]. Methods Mol Biol, 2019, 1950: 249-262. DOI: 10.1007/978-1-4939-9139-6_14.
77. Patel LN, Zaro JL, Shen WC. Cell penetrating peptides: intracellular pathways and pharmaceutical perspectives[J]. Pharm Res, 2007, 24(11): 1977-1992. DOI: 10.1007/s11095-007-9303-7.
78. Liu C, Tai L, Zhang W, et al. Penetratin, a potentially powerful absorption enhancer for noninvasive intraocular drug delivery[J]. Mol Pharm, 2014, 11(4): 1218-1227. DOI: 10.1021/mp400681n.
79. Jiang K, Hu Y, Gao X, et al. Octopus-like flexible vector for noninvasive intraocular delivery of short interfering nucleic acids[J]. Nano Lett, 2019, 19(9): 6410-6417. DOI: 10.1021/acs.nanolett.9b02596.
80. Liu X, Wu J, Yammine M, et al. Structurally flexible triethanolamine core PAMAM dendrimers are effective nanovectors for DNA transfection in vitro and in vivo to the mouse thymus[J]. Bioconjug Chem, 2011, 22(12): 2461-2473. DOI: 10.1021/bc200275g.
81. Barar J, Javadzadeh AR, Omidi Y. Ocular novel drug delivery: impacts of membranes and barriers[J]. Expert Opin Drug Deliv, 2008, 5(5): 567-581. DOI: 10.1517/17425247.5.5.567.
82. Liu C, Jiang K, Tai L, et al. Facile noninvasive retinal gene delivery enabled by penetratin[J]. ACS Appl Mater Interfaces, 2016, 8(30): 19256-19267. DOI: 10.1021/acsami.6b04551.
83. Tai L, Liu C, Jiang K, et al. A novel penetratin-modified complex for noninvasive intraocular delivery of antisense oligonucleotides[J]. Int J Pharm, 2017, 529(1-2): 347-356. DOI: 10.1016/j.ijpharm.2017.06.090.

Chinese Journal of Ocular Fundus Diseases

The status and progress of gene therapy delivery techniques for retinal diseases

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