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Review

Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses

Hashem H GhorabaSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Amir AkhavanrezayatSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Irmak KaracaSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAORCID Iconhttps://orcid.org/0000-0001-7927-0887View further author information
ORCID Icon,
Negin YavariSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Sherin LajevardiSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Jaclyn HwangSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAORCID Iconhttps://orcid.org/0000-0001-7756-3918View further author information
ORCID Icon,
Jonathan RegenoldSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Wataru MatsumiyaSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Brandon PhamSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Moosa ZaidiSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Azadeh MobasserianSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Anthony Toan DongChauSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Christopher OrSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Cigdem YasarSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAORCID Iconhttps://orcid.org/0000-0003-0386-3613View further author information
ORCID Icon,
Kapil MishraSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
,
Diana DoSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USAView further author information
&
Quan Dong NguyenSpencer Center for Vision Research, Byers Eye Institute, Stanford University, Palo Alto, CA, USACorrespondence[email protected]
View further author information
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Pages 1753-1771 | Published online: 03 Jun 2022

References

  • Ramamoorth M, Narvekar A. Non viral vectors in gene therapy- an overview. J Clin Diagn Res. 2015;9(1):GE01–GE06. doi:10.7860/JCDR/2015/10443.5394
  • Guimaraes TAC, Georgiou M, Bainbridge JWB, Michaelides M. Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. Br J Ophthalmol. 2020;105:151–157. doi:10.1136/bjophthalmol-2020-316195
  • Bennett J. Immune response following intraocular delivery of recombinant viral vectors. Gene Ther. 2003;10(11):977–982. doi:10.1038/sj.gt.3302030
  • 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. Lancet. 2017;390(10097):849–860. doi:10.1016/S0140-6736(17)31868-8
  • Li Z, Dullmann J, Schiedlmeier B, et al. Murine leukemia induced by retroviral gene marking. Science. 2002;296(5567):497. doi:10.1126/science.1068893
  • Bordet T, Behar-Cohen F. Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives. Drug Discov Today. 2019;24(8):1685–1693. doi:10.1016/j.drudis.2019.05.038
  • Rodrigues GA, Shalaev E, Karami TK, Cunningham J, Slater NKH, Rivers HM. Pharmaceutical development of AAV-based gene therapy products for the eye. Pharm Res. 2018;36(2):29. doi:10.1007/s11095-018-2554-7
  • Gregory SM, Nazir SA, Metcalf JP. Implications of the innate immune response to adenovirus and adenoviral vectors. Future Virol. 2011;6(3):357–374. doi:10.2217/fvl.11.6
  • Raper SE, Chirmule N, Lee FS, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80(1–2):148–158. doi:10.1016/j.ymgme.2003.08.016
  • Roth JA, Cristiano RJ. Gene therapy for cancer: what have we done and where are we going? J Natl Cancer Inst. 1997;89(1):21–39. doi:10.1093/jnci/89.1.21
  • Bastola P, Song L, Gilger BC, Hirsch ML. Adeno-associated virus mediated gene therapy for corneal diseases. Pharmaceutics. 2020;12(8):767. doi:10.3390/pharmaceutics12080767
  • Lebherz C, Maguire A, Tang W, Bennett J, Wilson JM. Novel AAV serotypes for improved ocular gene transfer. J Gene Med. 2008;10(4):375–382. doi:10.1002/jgm.1126
  • Reichel FF, Dauletbekov DL, Klein R, et al. AAV8 can induce innate and adaptive immune response in the primate eye. Mol Ther. 2017;25(12):2648–2660. doi:10.1016/j.ymthe.2017.08.018
  • Fischer MD, Michalakis S, Wilhelm B, et al. Safety and vision outcomes of subretinal gene therapy targeting cone photoreceptors in achromatopsia: a nonrandomized controlled trial. JAMA Ophthalmol. 2020;138(6):643–651. doi:10.1001/jamaophthalmol.2020.1032
  • Liu MM, Tuo J, Chan CC. Gene therapy for ocular diseases. Br J Ophthalmol. 2011;95(5):604–612. doi:10.1136/bjo.2009.174912
  • Timmers AM, Newmark JA, Turunen HT, et al. Ocular inflammatory response to intravitreal injection of adeno-associated virus vector: relative contribution of genome and capsid. Hum Gene Ther. 2020;31(1–2):80–89. doi:10.1089/hum.2019.144
  • Pepose JS, Leib DA. Herpes simplex viral vectors for therapeutic gene delivery to ocular tissues. Recent breakthroughs in the molecular genetics of ocular diseases. Invest Ophthalmol Vis Sci. 1994;35(6):2662–2666.
  • Buck TM, Wijnholds J. Recombinant Adeno-Associated Viral Vectors (rAAV)-vector elements in ocular gene therapy clinical trials and transgene expression and bioactivity assays. Int J Mol Sci. 2020;21(12):4197. doi:10.3390/ijms21124197
  • Anand V, Duffy B, Yang Z, Dejneka NS, Maguire AM, Bennett J. A deviant immune response to viral proteins and transgene product is generated on subretinal administration of adenovirus and adeno-associated virus. Mol Ther. 2002;5(2):125–132. doi:10.1006/mthe.2002.0525
  • Boutin S, Monteilhet V, Veron P, et al. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther. 2010;21(6):704–712. doi:10.1089/hum.2009.182
  • Kotterman MA, Yin L, Strazzeri JM, Flannery JG, Merigan WH, Schaffer DV. Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates. Gene Ther. 2015;22(2):116–126. doi:10.1038/gt.2014.115
  • Wan C, Li F, Li H. Gene therapy for ocular diseases mediated by ultrasound and microbubbles (Review). Mol Med Rep. 2015;12(4):4803–4814. doi:10.3892/mmr.2015.4054
  • Balaggan KS, Ali RR. Ocular gene delivery using lentiviral vectors. Gene Ther. 2012;19(2):145–153. doi:10.1038/gt.2011.153
  • Philippe S, Sarkis C, Barkats M, et al. Lentiviral vectors with a defective integrase allow efficient and sustained transgene expression in vitro and in vivo. Proc Natl Acad Sci U S A. 2006;103(47):17684–17689. doi:10.1073/pnas.0606197103
  • Nuzbrokh Y, Kassotis AS, Ragi SD, Jauregui R, Tsang SH. Treatment-emergent adverse events in gene therapy trials for inherited retinal diseases: a narrative review. Ophthalmol Ther. 2020;9(4):709–724. doi:10.1007/s40123-020-00287-1
  • Jiang J, Zhang X, Tang Y, Li S, Chen J. Progress on ocular siRNA gene-silencing therapy and drug delivery systems. Fundam Clin Pharmacol. 2020;35:4–24. doi:10.1111/fcp.12561
  • Kalesnykas G, Kokki E, Alasaarela L, et al. Comparative study of adeno-associated virus, adenovirus, bacu lovirus and lentivirus vectors for gene therapy of the eyes. Curr Gene Ther. 2017;17(3):235–247. doi:10.2174/1566523217666171003170348
  • 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. Invest Ophthalmol Vis Sci. 2013;54(6):4061–4071. doi:10.1167/iovs.13-11871
  • Binley K, Widdowson PS, Kelleher M, et al. Safety and biodistribution of an equine infectious anemia virus-based gene therapy, RetinoStat((R)), for age-related macular degeneration. Hum Gene Ther. 2012;23(9):980–991. doi:10.1089/hum.2012.008
  • Campochiaro PA, Lauer AK, Sohn EH, et al. Lentiviral vector gene transfer of endostatin/angiostatin for Macular Degeneration (GEM) Study. Hum Gene Ther. 2017;28(1):99–111. doi:10.1089/hum.2016.117
  • Bloquel C, Bourges JL, Touchard E, Berdugo M, BenEzra D, Behar-Cohen F. Non-viral ocular gene therapy: potential ocular therapeutic avenues. Adv Drug Deliv Rev. 2006;58(11):1224–1242. doi:10.1016/j.addr.2006.07.023
  • Oliveira AV, Rosa da Costa AM, Silva GA. Non-viral strategies for ocular gene delivery. Mater Sci Eng C Mater Biol Appl. 2017;77:1275–1289. doi:10.1016/j.msec.2017.04.068
  • Kowalczuk L, Touchard E, Camelo S, et al. Local ocular immunomodulation resulting from electrotransfer of plasmid encoding soluble TNF receptors in the ciliary muscle. Invest Ophthalmol Vis Sci. 2009;50(4):1761–1768. doi:10.1167/iovs.08-3027
  • Solinis MA, Del Pozo-Rodriguez A, Apaolaza PS, Rodriguez-Gascon A. Treatment of ocular disorders by gene therapy. Eur J Pharm Biopharm. 2015;95(Pt B):331–342. doi:10.1016/j.ejpb.2014.12.022
  • Di Iorio E, Barbaro V, Alvisi G, et al. New frontiers of corneal gene therapy. Hum Gene Ther. 2019;30(8):923–945. doi:10.1089/hum.2019.026
  • Bettin P, Di Matteo F. Glaucoma: present challenges and future trends. Ophthalmic Res. 2013;50(4):197–208. doi:10.1159/000348736
  • Bucolo C, Salomone S, Drago F, Reibaldi M, Longo A, Uva MG. Pharmacological management of ocular hypertension: current approaches and future prospective. Curr Opin Pharmacol. 2013;13(1):50–55. doi:10.1016/j.coph.2012.09.012
  • Moreno-Montanes J, Sadaba B, Ruz V, et al. Phase I clinical trial of SYL040012, a small interfering RNA targeting beta-adrenergic receptor 2, for lowering intraocular pressure. Mol Ther. 2014;22(1):226–232. doi:10.1038/mt.2013.217
  • Naik S, Shreya AB, Raychaudhuri R, et al. Small interfering RNAs (siRNAs) based gene silencing strategies for the treatment of glaucoma: recent advancements and future perspectives. Life Sci. 2021;264:118712. doi:10.1016/j.lfs.2020.118712
  • Byrne LC, Ozturk BE, Lee T, et al. Retinoschisin gene therapy in photoreceptors, Muller glia or all retinal cells in the Rs1h-/- mouse. Gene Ther. 2014;21(6):585–592. doi:10.1038/gt.2014.31
  • 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. Mol Ther. 2018;26(9):2282–2294. doi:10.1016/j.ymthe.2018.05.025
  • Han Z, Conley SM, Naash MI. Gene therapy for Stargardt disease associated with ABCA4 gene. Adv Exp Med Biol. 2014;801:719–724.
  • Parker MA, Choi D, Erker LR, et al. Test-retest variability of functional and structural parameters in patients with Stargardt disease participating in the SAR422459 gene therapy trial. Transl Vis Sci Technol. 2016;5(5):10. doi:10.1167/tvst.5.5.10
  • Seabra MC, Brown MS, Slaughter CA, Sudhof TC, Goldstein JL. Purification of component A of Rab geranylgeranyl transferase: possible identity with the choroideremia gene product. Cell. 1992;70(6):1049–1057. doi:10.1016/0092-8674(92)90253-9
  • Dimopoulos IS, Chan S, MacLaren RE, MacDonald IM. Pathogenic mechanisms and the prospect of gene therapy for choroideremia. Expert Opin Orphan Drugs. 2015;3(7):787–798. doi:10.1517/21678707.2015.1046434
  • Vasireddy V, Mills JA, Gaddameedi R, et al. Correction: AAV-mediated gene therapy for choroideremia: preclinical studies in personalized models. PLoS One. 2015;10(6):e0129982. doi:10.1371/journal.pone.0129982
  • MacDonald IM, Moen C, Duncan JL, Tsang SH, Cehajic-Kapetanovic J, Aleman TS. Perspectives on gene therapy: choroideremia represents a challenging model for the treatment of other inherited retinal degenerations. Transl Vis Sci Technol. 2020;9(3):17. doi:10.1167/tvst.9.3.17
  • Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368(9549):1795–1809. doi:10.1016/S0140-6736(06)69740-7
  • Zhang Q. Retinitis pigmentosa: progress and perspective. Asia Pac J Ophthalmol. 2016;5(4):265–271. doi:10.1097/APO.0000000000000227
  • Simunovic MP, Shen W, Lin JY, Protti DA, Lisowski L, Gillies MC. Optogenetic approaches to vision restoration. Exp Eye Res. 2019;178:15–26. doi:10.1016/j.exer.2018.09.003
  • Mathur P, Yang J. Usher syndrome: hearing loss, retinal degeneration and associated abnormalities. Biochim Biophys Acta. 2015;1852(3):406–420. doi:10.1016/j.bbadis.2014.11.020
  • Hashimoto T, Gibbs D, Lillo C, et al. Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B. Gene Ther. 2007;14(7):584–594. doi:10.1038/sj.gt.3302897
  • Weleber R, Sahel J. Study of SAR421869 in participants with retinitis pigmentosa associated with usher syndrome type 1B. Identifier: NCT01505062; 2012. Available from: https://ClinicalTrials.gov/show/NCT01505062. Accessed May 26, 2022.
  • National Library of Medicine (U.S.). Study to evaluate safety and tolerability of QR-421a in subjects with RP due to mutations in Exon 13 of the USH2A gene. Identifier NCT03780257; 2018. Available from: https://clinicaltrials.gov/ct2/show/NCT03780257. Accessed May 26, 2022.
  • Thiadens AA, Slingerland NW, Roosing S, et al. Genetic etiology and clinical consequences of complete and incomplete achromatopsia. Ophthalmology. 2009;116(10):1984–1989 e1981. doi:10.1016/j.ophtha.2009.03.053
  • Chung DC, Traboulsi EI. Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J AAPOS. 2009;13(6):587–592. doi:10.1016/j.jaapos.2009.10.004
  • National Library of Medicine (U.S.). ADVM-022 intravitreal gene therapy for wet AMD. Identifier NCT03748784. 2018. Available from: https://clinicaltrials.gov/ct2/show/NCT03748784. Accessed May 26, 2022.
  • National Library of Medicine (U.S.). RGX-314 gene therapy administered in the suprachoroidal space for participants with Diabetic Retinopathy (DR) without Center Involved-Diabetic Macular Edema (CI-DME) (ALTITUDE). Identifier NCT04567550; 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT04567550. Accessed May 26, 2022.
  • National Library of Medicine (U.S.). ADVM-022 Intravitreal Gene Therapy for DME (INFINITY). Identifier NCT04418427; 2020. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04418427. Accessed May 26, 2022.
  • Cwerman-Thibault H, Augustin S, Ellouze S, Sahel JA, Corral-Debrinski M. Gene therapy for mitochondrial diseases: Leber Hereditary Optic Neuropathy as the first candidate for a clinical trial. C R Biol. 2014;337(3):193–206. doi:10.1016/j.crvi.2013.11.011
  • Bonnet C, Augustin S, Ellouze S, et al. The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes. Biochim Biophys Acta. 2008;1783(10):1707–1717. doi:10.1016/j.bbamcr.2008.04.018
  • Wan X, Pei H, Zhao MJ, et al. Efficacy and safety of rAAV2-ND4 treatment for Leber’s hereditary optic neuropathy. Sci Rep. 2016;6:21587. doi:10.1038/srep21587
  • Feuer WJ, Schiffman JC, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: initial results. Ophthalmology. 2016;123(3):558–570. doi:10.1016/j.ophtha.2015.10.025
  • Guy J, Feuer WJ, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: low- and medium-dose visual results. Ophthalmology. 2017;124(11):1621–1634. doi:10.1016/j.ophtha.2017.05.016
  • 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. Sci Transl Med. 2013;5(189):189ra176. doi:10.1126/scitranslmed.3005708
  • Klimczak RR, Koerber JT, Dalkara D, Flannery JG, Schaffer DV. A novel adeno-associated viral variant for efficient and selective intravitreal transduction of rat Muller cells. PLoS One. 2009;4(10):e7467. doi:10.1371/journal.pone.0007467
  • Boye SE, Boye SL, Lewin AS, Hauswirth WW. A comprehensive review of retinal gene therapy. Mol Ther. 2013;21(3):509–519. doi:10.1038/mt.2012.280
  • 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. Mol Ther. 2017;25(1):296–302. doi:10.1016/j.ymthe.2016.10.008
  • Dalkara D, Kolstad KD, Caporale N, et al. Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous. Mol Ther. 2009;17(12):2096–2102. doi:10.1038/mt.2009.181
  • Byrne LC, Day TP, Visel M, et al. In vivo-directed evolution of adeno-associated virus in the primate retina. JCI Insight. 2020;5(10). doi:10.1172/jci.insight.135112
  • Sonoda KH, Sakamoto T, Qiao H, et al. The analysis of systemic tolerance elicited by antigen inoculation into the vitreous cavity: vitreous cavity-associated immune deviation. Immunology. 2005;116(3):390–399. doi:10.1111/j.1365-2567.2005.02239.x
  • Jiang LQ, Streilein JW. Immune privilege extended to allogeneic tumor cells in the vitreous cavity. Invest Ophthalmol Vis Sci. 1991;32(1):224–228.
  • Atherton SS, Pesicka GA, Streilein JW. Retinitis and deviant immune responses following intravitreal inoculation of HSV-1. Invest Ophthalmol Vis Sci. 1987;28(5):859–866.
  • Reichel FF, Peters T, Wilhelm B, et al. Humoral immune response after intravitreal but not after subretinal AAV8 in primates and patients. Invest Ophthalmol Vis Sci. 2018;59(5):1910–1915. doi:10.1167/iovs.17-22494
  • Li Q, Miller R, Han PY, et al. Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential. Mol Vis. 2008;14:1760–1769.
  • Marangoni D, Wu Z, Wiley HE, et al. Preclinical safety evaluation of a recombinant AAV8 vector for X-linked retinoschisis after intravitreal administration in rabbits. Hum Gene Ther Clin Dev. 2014;25(4):202–211. doi:10.1089/humc.2014.067
  • Ramachandran PS, Lee V, Wei Z, et al. Evaluation of dose and safety of AAV7m8 and AAV8BP2 in the non-human primate retina. Hum Gene Ther. 2017;28(2):154–167. doi:10.1089/hum.2016.111
  • Yiu G, Chung SH, Mollhoff IN, et al. Suprachoroidal and subretinal injections of AAV using transscleral microneedles for retinal gene delivery in nonhuman primates. Mol Ther Methods Clin Dev. 2020;16:179–191. doi:10.1016/j.omtm.2020.01.002
  • Bouquet C, Vignal Clermont C, Galy A, et al. Immune response and intraocular inflammation in patients with Leber hereditary optic neuropathy treated with intravitreal injection of recombinant adeno-associated virus 2 carrying the ND4 gene: a secondary analysis of a phase 1/2 clinical trial. JAMA Ophthalmol. 2019;137(4):399–406. doi:10.1001/jamaophthalmol.2018.6902
  • Wykoff Obotii CC. Intravitreal gene therapy for diabetic macular edema with ADVM-022: first-time data presentation of prospective, randomized phase 2 INFINITY trial [Conference presentation]. American Society of Retina Specialists Annual Scientific Meeting; October 8-12, 2021; 2021; San Antonio, Texas, USA.
  • Dante Pieramici O. ADVM-022 intravitreal gene therapy for neovascular AMD: phase 1 OPTIC study [Conference presentation]. American Society of Retina Specialists Annual Scientific Meeting; October 8-12, 2021; 2021; San Antonio, Texas, USA.
  • Rubsam A, Parikh S, Fort PE. Role of inflammation in diabetic retinopathy. Int J Mol Sci. 2018;19(4):942. doi:10.3390/ijms19040942
  • Xue K, Groppe M, Salvetti AP, MacLaren RE. Technique of retinal gene therapy: delivery of viral vector into the subretinal space. Eye. 2017;31(9):1308–1316. doi:10.1038/eye.2017.158
  • Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19(10):979–990. doi:10.1089/hum.2008.107
  • 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. Invest Ophthalmol Vis Sci. 2017;58(13):5792–5801. doi:10.1167/iovs.17-22473
  • Manfredi A, Marrocco E, Puppo A, et al. Combined rod and cone transduction by adeno-associated virus 2/8. Hum Gene Ther. 2013;24(12):982–992. doi:10.1089/hum.2013.154
  • Constable IJ, Pierce CM, Lai CM, et al. Phase 2a randomized clinical trial: safety and post hoc analysis of subretinal rAAV.sFLT-1 for wet age-related macular degeneration. EBioMedicine. 2016;14:168–175. doi:10.1016/j.ebiom.2016.11.016
  • Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2240–2248. doi:10.1056/NEJMoa0802315
  • Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012;130(1):9–24. doi:10.1001/archophthalmol.2011.298
  • Ochakovski GA, Peters T, Michalakis S, et al. Subretinal injection for gene therapy does not cause clinically significant outer nuclear layer thinning in normal primate foveae. Invest Ophthalmol Vis Sci. 2017;58(10):4155–4160. doi:10.1167/iovs.17-22402
  • Bucher K, Rodriguez-Bocanegra E, Dauletbekov D, Fischer MD. Immune responses to retinal gene therapy using adeno-associated viral vectors - implications for treatment success and safety. Prog Retin Eye Res. 2020;83:100915. doi:10.1016/j.preteyeres.2020.100915
  • Weed L, Ammar MJ, Zhou S, et al. Safety of same-eye subretinal sequential readministration of AAV2-hRPE65v2 in non-human primates. Mol Ther Methods Clin Dev. 2019;15:133–148. doi:10.1016/j.omtm.2019.08.011
  • Dimopoulos IS, Hoang SC, Radziwon A, et al. Two-year results after AAV2-mediated gene therapy for choroideremia: the Alberta experience. Am J Ophthalmol. 2018;193:130–142. doi:10.1016/j.ajo.2018.06.011
  • Shen J, Kim J, Tzeng SY, et al. Suprachoroidal gene transfer with nonviral nanoparticles. Sci Adv. 2020;6(27). doi:10.1126/sciadv.aba1606
  • Peden MC, Min J, Meyers C, et al. Ab-externo AAV-mediated gene delivery to the suprachoroidal space using a 250 micron flexible microcatheter. PLoS One. 2011;6(2):e17140. doi:10.1371/journal.pone.0017140
  • Olsen TW, Feng X, Wabner K, et al. Cannulation of the suprachoroidal space: a novel drug delivery methodology to the posterior segment. Am J Ophthalmol. 2006;142(5):777–787. doi:10.1016/j.ajo.2006.05.045
  • Rizzo S, Ebert FG, Bartolo ED, et al. Suprachoroidal drug infusion for the treatment of severe subfoveal hard exudates. Retina. 2012;32(4):776–784. doi:10.1097/IAE.0b013e3182278b0e
  • Chen M, Li X, Liu J, Han Y, Cheng L. Safety and pharmacodynamics of suprachoroidal injection of triamcinolone acetonide as a controlled ocular drug release model. J Control Release. 2015;203:109–117. doi:10.1016/j.jconrel.2015.02.021
  • 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. Ophthalmology. 2020;127(7):948–955. doi:10.1016/j.ophtha.2020.01.006
  • Barakat MR, Wykoff CC, Gonzalez V, et al. Aflibercept with or without suprachoroidal CLS-TA for diabetic macular edema: a randomized, double-masked, parallel-design, controlled study. Ophthalmol Retina. 2020;5:60–70. doi:10.1016/j.oret.2020.08.007
  • Ding K, Shen J, Hafiz Z, et al. AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression. J Clin Invest. 2019;129(11):4901–4911. doi:10.1172/JCI129085
  • Touchard E, Benard R, Bigot K, et al. Non-viral ocular gene therapy, pEYS606, for the treatment of non-infectious uveitis: preclinical evaluation of the medicinal product. J Control Release. 2018;285:244–251. doi:10.1016/j.jconrel.2018.07.013
  • Touchard E, Berdugo M, Bigey P, et al. Suprachoroidal electrotransfer: a nonviral gene delivery method to transfect the choroid and the retina without detaching the retina. Mol Ther. 2012;20(8):1559–1570. doi:10.1038/mt.2011.304
  • Chalberg TW, Vankov A, Molnar FE, et al. Gene transfer to rabbit retina with electron avalanche transfection. Invest Ophthalmol Vis Sci. 2006;47(9):4083–4090. doi:10.1167/iovs.06-0092
  • Chan YK, Dick AD, Hall SM, et al. Inflammation in viral vector-mediated ocular gene therapy: a review and report from a workshop hosted by the foundation fighting blindness, 9/2020. Transl Vis Sci Technol. 2021;10(4):3. doi:10.1167/tvst.10.4.3
  • Bucher K, Rodriguez-Bocanegra E, Dauletbekov D, Fischer MD. Immune responses to retinal gene therapy using adeno-associated viral vectors - implications for treatment success and safety. Prog Retin Eye Res. 2021;83:100915.
  • Mehta N, Robbins DA, Yiu G. Ocular inflammation and treatment emergent adverse events in retinal gene therapy. Int Ophthalmol Clin. 2021;61(3):151–177. doi:10.1097/IIO.0000000000000366
  • Le Meur G, Lebranchu P, Billaud F, et al. Safety and long-term efficacy of AAV4 gene therapy in patients with RPE65 Leber congenital amaurosis. Mol Ther. 2018;26(1):256–268. doi:10.1016/j.ymthe.2017.09.014
  • Zack DJ. Ocular gene therapy. From fantasy to foreseeable reality. Arch Ophthalmol. 1993;111(11):1477–1479. doi:10.1001/archopht.1993.01090110043019

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