{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T04:36:11Z","timestamp":1793162171227,"version":"4.5.0"},"reference-count":76,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","license":[{"start":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T00:00:00Z","timestamp":1611532800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Inherited retinal degenerations are a leading and untreatbale cause of blindness, and as such they are targets for gene therapy. Numerous gene therapy treatments have progressed from laboratory research to clinical trails, and a pioneering gene therapy received the first ever FDA approval for treating patients. However, currently retinal gene therapy mostly involves subretinal injection of the therapeutic agent, which treats a limited area, entails retinal detachment and other potential complications, and requires general anesthesia with consequent risks, costs and prolonged recovery. Therefore there is great impetus to develop safer, less invasive and cheapter methods of gene delivery. A promising method is intravitreal injection, that does not cause retinal detachment, can lead to pan-retinal transduction and can be performed under local anesthesia in out-patient clinics. Intravitreally-injected vectors face several obstacles. First, the vector is diluted by the vitreous and has to overcome a long diffusion distance to the target cells. Second, the vector is exposed to the host\u2019s immune response, risking neutralization by pre-existing antibodies and triggering a stronger immune response to the injection. Third, the vector has to cross the inner limiting membrane which is both a physical and a biological barrier as it contains binding sites that could cause the vector\u2019s sequestration. Finally, in the target cell the vector is prone to proteasome degradation before delivering the transgene to the nucleus. Strategies to overcome these obstacles include modifications of the viral capsid, through rational design or directed evolution, which allow resistance to the immune system, enhancement of penetration through the inner limiting membrane or reduced degradation by intracellular proteasomes. Furthermore, physical and chemical manipulations of the inner limiting membrane and vitreous aim to improve vector penetration. Finally, compact non-viral vectors that can overcome the immunological, physical and anatomical and barriers have been developed. This paper reviews ongoing efforts to develop novel, safe and efficacious methods for intravitreal delivery of therapeutic genes for inherited retinal degenerations. To date, the most promising results are achieved in rodents with robust, pan-retinal transduction following intravitreal delivery. Trials in larger animal models demonstrate transduction mostly of inner retinal layers. Despite ongoing efforts, currently no intravitreally-injected vector has demonstrated outer retinal transduction efficacy comparable to that of subretinal delivery. Further work is warranted to test promising new viral and non-viral vectors on large animal models of inherited retinal degenerations. Positive results will pave the way to development of the next generation of treatments for inherited retinal degeneration.<\/jats:p>","DOI":"10.4103\/1673-5374.306063","type":"journal-article","created":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T05:43:17Z","timestamp":1611639797000},"page":"1751-1759","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":70,"title":["The future of retinal gene therapy: evolving from subretinal to intravitreal vector delivery"],"prefix":"10.4103","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6525-7032","authenticated-orcid":false,"given":"Maya","family":"Ross","sequence":"first","affiliation":[{"name":"Koret School of Veterinary Medicine, The Hebrew University of Jerusalem, Rehovot, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3825-3113","authenticated-orcid":false,"given":"Ron","family":"Ofri","sequence":"additional","affiliation":[{"name":"Koret School of Veterinary Medicine, The Hebrew University of Jerusalem, Rehovot, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,9]]},"reference":[{"key":"R1-20260525","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.ejpb.2014.12.028","article-title":"Nanoparticle-based technologies for retinal gene therapy","volume":"95","author":"Adijanto","year":"2015","journal-title":"Eur J Pharm Biopharm"},{"key":"R2-20260525","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1089\/hum.1998.9.1-81","article-title":"Adeno-associated virus gene transfer to mouse retina","volume":"9","author":"Ali","year":"1998","journal-title":"Hum Gene Ther"},{"key":"R3-20260525","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/mt.2015.114","article-title":"Gene augmentation therapy restores retinal function and visual behavior in a sheep model of CNGA3 achromatopsia","volume":"23","author":"Banin","year":"2015","journal-title":"Mol Ther"},{"key":"R4-20260525","doi-asserted-by":"crossref","first-page":"107433","DOI":"10.1016\/j.jsb.2019.107433","article-title":"Structure comparison of the chimeric AAV2.7m8 vector with parental AAV2","volume":"209","author":"Bennett","year":"2020","journal-title":"J Struct Biol"},{"key":"R5-20260525","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/j.drudis.2019.05.038","article-title":"Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives","volume":"24","author":"Bordet","year":"2019","journal-title":"Drug Discov Today"},{"key":"R6-20260525","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/gt.2015.96","article-title":"Photoreceptor-targeted gene delivery using intravitreally administered AAV vectors in dogs","volume":"23","author":"Boyd","year":"2016","journal-title":"Gene Ther"},{"key":"R7-20260525","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/gt.2016.31","article-title":"Reduced retinal transduction and enhanced transgene-directed immunogenicity with intravitreal delivery of rAAV following posterior vitrectomy in dogs","volume":"23","author":"Boyd","year":"2016","journal-title":"Gene Ther"},{"key":"R8-20260525","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1128\/JVI.00200-16","article-title":"Impact of heparan sulfate binding on transduction of retina by recombinant adeno-associated virus vectors","volume":"90","author":"Boye","year":"2016","journal-title":"J Virol"},{"key":"R9-20260525","doi-asserted-by":"crossref","first-page":"e135112","DOI":"10.1172\/jci.insight.135112","article-title":"In vivo-directed evolution of adeno-associated virus in the primate retina","volume":"5","author":"Byrne","year":"2020","journal-title":"JCI Insight"},{"key":"R10-20260525","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1086\/595830","article-title":"Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses","volume":"199","author":"Calcedo","year":"2009","journal-title":"J Infect Dis"},{"key":"R11-20260525","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1128\/CVI.05107-11","article-title":"Adeno-associated virus antibody profiles in newborns, children, and adolescents","volume":"18","author":"Calcedo","year":"2011","journal-title":"Clin Vaccine Immunol"},{"key":"R12-20260525","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/gt.2014.7","article-title":"Effect of bortezomib on the efficacy of AAV9. 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