This is a preview of subscription content, access via your institution
Relevant articles
Open Access articles citing this article.
-
Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration
Journal of Neuroinflammation Open Access 22 January 2021
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
High KA, Roncarolo MG. Gene therapy. N Engl J Med. 2019;381:455–64.
Trapani I, Auricchio A. Seeing the light after 25 years of retinal gene therapy. Trends Mol Med. 2018;24:669–81.
Garafalo AV, Cideciyan AV, Heon E, Sheplock R, Pearson A, WeiYang Yu C, et al. Progress in treating inherited retinal diseases: early subretinal gene therapy clinical trials and candidates for future initiatives. Prog Retin Eye Res. 2019:100827. [Online ahead of print].
Trapani I, Auricchio A. Has retinal gene therapy come of age? From bench to bedside and back to bench. Hum Mol Genet. 2019;28:R108–18.
Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, 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;390:849–60.
Drack AV, Bennett J, Russel S, High KA, Yu ZF, Tillman A, et al. How long does gene therapy last? 4 Year follow-up of phase 3 voretigene neparvo-vec trial in RPE65-associated LCA/inherited retinal disease. Presented at the American Association for Pediatric Ophthalmology and Strabismus 45th Annual Meeting, San Diego, CA; 2019.
Dimopoulos IS, Hoang SC, Radziwon A, Binczyk NM, Seabra MC, MacLaren RE, et al. Two-year results after AAV2-mediated gene therapy for choroideremia: the Alberta experience. Am J Ophthalmol. 2018;193:130–42.
Moore NA, Morral N, Ciulla TA, Bracha P. Gene therapy for inherited retinal and optic nerve degenerations. Expert Opin Biol Ther. 2018;18:37–49.
Vignal C, Uretsky S, Fitoussi S, Galy A, Blouin L, Girmens JF, et al. Safety of rAAV2/2-ND4 gene therapy for Leber hereditary optic neuropathy. Ophthalmology. 2018;125:945–7.
Ghazi NG, Abboud EB, Nowilaty SR, Alkuraya H, Alhommadi A, Cai H, 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. Hum Genet. 2016;135:327–43.
Xue K, Jolly JK, Barnard AR, Rudenko A, Salvetti AP, Patricio MI, et al. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med. 2018;24:1507–12.
Lam BL, Davis JL, Gregori NZ, MacLaren RE, Girach A, Verriotto JD, et al. Choroideremia gene therapy phase 2 clinical trial: 24-month results. Am J Ophthalmol. 2019;197:65–73.
Simunovic MP, Xue K, Jolly JK, MacLaren RE. Structural and functional recovery following limited iatrogenic macular detachment for retinal gene therapy. JAMA Ophthalmol. 2017;135:234–41.
Edwards TL, Xue K, Meenink HCM, Beelen MJ, Naus GJL, Simunovic MP, et al. First-in-human study of the safety and viability of intraocular robotic surgery. Nat Biomed Eng. 2018;2:649–56.
Campochiaro PA, Mir TA. The mechanism of cone cell death in Retinitis Pigmentosa. Prog Retin Eye Res. 2018;62:24–37.
Lang M, Harris A, Ciulla TA, Siesky B, Patel P, Belamkar A, et al. Vascular dysfunction in retinitis pigmentosa. Acta Ophthalmol. 2019;97:660–4.
Bennett J, Wellman J, Marshall KA, McCague S, Ashtari M, DiStefano-Pappas J, et al. Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet. 2016;388:661–72.
Maguire AM, Russell S, Wellman JA, Chung DC, Yu ZF, Tillman A, et al. Efficacy, safety, and durability of voretigene neparvovec-rzyl in RPE65 mutation-associated inherited retinal dystrophy: results of phase 1 and 3 trials. Ophthalmology. 2019;126:1273–85.
Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, et al. Long-term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med. 2015;372:1887–97.
Jacobson SG, Cideciyan AV, Roman AJ, Sumaroka A, Schwartz SB, Heon E, et al. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med. 2015;372:1920–6.
Katada Y, Kobayashi K, Tsubota K, Kurihara T. Evaluation of AAV-DJ vector for retinal gene therapy. PeerJ. 2019;7:e6317.
Khabou H, Desrosiers M, Winckler C, Fouquet S, Auregan G, Bemelmans AP, et al. Insight into the mechanisms of enhanced retinal transduction by the engineered AAV2 capsid variant—7m8. Biotechnol Bioeng. 2016;113:2712–24.
Zeng Y, Qian H, Wu Z, Marangoni D, Sieving PA, Bush RA. AAVrh-10 transduces outer retinal cells in rodents and rabbits following intravitreal administration. Gene Ther. 2019;26:386–98.
Weed L, Ammar MJ, Zhou S, Wei Z, Serrano LW, Sun J, et al. Safety of same-eye subretinal sequential readministration of AAV2-hRPE65v2 in non-human primates. Mol Ther Methods Clin Dev. 2019;15:133–48.
Yang S, Ma SQ, Wan X, He H, Pei H, Zhao MJ, et al. Long-term outcomes of gene therapy for the treatment of Leber’s hereditary optic neuropathy. EBioMedicine. 2016;10:258–68.
Cukras C, Wiley HE, Jeffrey BG, Sen HN, Turriff A, Zeng Y, 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;26:2282–94.
Zhong L, Li B, Jayandharan G, Mah CS, Govindasamy L, Agbandje-McKenna M, et al. Tyrosine-phosphorylation of AAV2 vectors and its consequences on viral intracellular trafficking and transgene expression. Virology. 2008;381:194–202.
Li Q, Miller R, Han PY, Pang J, Dinculescu A, Chiodo V, et al. Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential. Mol Vis. 2008;14:1760–9.
Heier JS, Kherani S, Desai S, Dugel P, Kaushal S, Cheng SH, et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet. 2017;390:50–61.
Corydon TJ. Antiangiogenic eye gene therapy. Hum Gene Ther. 2015;26:525–37.
Rakoczy EP, Magno AL, Lai CM, Pierce CM, Degli-Esposti MA, Blumenkranz MS, et al. Three-year follow-up of phase 1 and 2a rAAV.sFLT-1 subretinal gene therapy trials for exudative age-related macular degeneration. Am J Ophthalmol. 2019;204:113–23.
Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339:819–23.
Gasiunas G, Barrangou R, Horvath P, Siksnys V. Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proc Natl Acad Sci USA. 2012;109:E2579–86.
Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337:816–21.
Maeder ML, Stefanidakis M, Wilson CJ, Baral R, Barrera LA, Bounoutas GS, et al. Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10. Nat Med. 2019;25:229–33.
Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science. 2013;339:823–6.
Suzuki K, Tsunekawa Y, Hernandez-Benitez R, Wu J, Zhu J, Kim EJ, et al. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature. 2016;540:144–9.
Chen JS, Dagdas YS, Kleinstiver BP, Welch MM, Sousa AA, Harrington LB, et al. Enhanced proofreading governs CRISPR-Cas9 targeting accuracy. Nature. 2017;550:407–10.
Kleinstiver BP, Prew MS, Tsai SQ, Topkar VV, Nguyen NT, Zheng Z, et al. Engineered CRISPR-Cas9 nucleases with altered PAM specificities. Nature. 2015;523:481–5.
Slaymaker IM, Gao L, Zetsche B, Scott DA, Yan WX, Zhang F. Rationally engineered Cas9 nucleases with improved specificity. Science. 2016;351:84–8.
Wang D, Zhang C, Wang B, Li B, Wang Q, Liu D, et al. Optimized CRISPR guide RNA design for two high-fidelity Cas9 variants by deep learning. Nat Commun. 2019;10:4284.
Kim K, Park SW, Kim JH, Lee SH, Kim D, Koo T, et al. Genome surgery using Cas9 ribonucleoproteins for the treatment of age-related macular degeneration. Genome Res. 2017;27:419–26.
Mikkelsen JG. Viral delivery of genome-modifying proteins for cellular reprogramming. Curr Opin Genet Dev. 2018;52:92–9.
Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533:420–4.
Anzalone AV, Randolph PB, Davis JR, Sousa AA, Koblan LW, Levy JM, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature. 2019;576:149–57.
Dyka FM, Boye SL, Chiodo VA, Hauswirth WW, Boye SE. Dual adeno-associated virus vectors result in efficient in vitro and in vivo expression of an oversized gene, MYO7A. Hum Gene Ther Methods. 2014;25:166–77.
McClements ME, Barnard AR, Singh MS, Charbel Issa P, Jiang Z, Radu RA, et al. An AAV dual vector strategy ameliorates the stargardt phenotype in adult Abca4(−/−) mice. Hum Gene Ther. 2019;30:590–600.
Trapani I, Colella P, Sommella A, Iodice C, Cesi G, de Simone S, et al. Effective delivery of large genes to the retina by dual AAV vectors. EMBO Mol Med. 2014;6:194–211.
Binley K, Widdowson P, Loader J, Kelleher M, Iqball S, Ferrige G, et al. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease. Investig Ophthalmol Vis Sci. 2013;54:4061–71.
Osborne A, Khatib TZ, Songra L, Barber AC, Hall K, Kong GYX, et al. Neuroprotection of retinal ganglion cells by a novel gene therapy construct that achieves sustained enhancement of brain-derived neurotrophic factor/tropomyosin-related kinase receptor-B signaling. Cell Death Dis. 2018;9:1007.
Biswal MR, Han P, Zhu P, Wang Z, Li H, Ildefonso CJ, et al. Timing of antioxidant gene therapy: implications for treating dry AMD. Investig Ophthalmol Vis Sci. 2017;58:1237–45.
Bainbridge JW, Tan MH, Ali RR. Gene therapy progress and prospects: the eye. Gene Ther. 2006;13:1191–7.
Askou AL, Alsing S, Benckendorff JNE, Holmgaard A, Mikkelsen JG, Aagaard L, et al. Suppression of choroidal neovascularization by AAV-based dual-acting antiangiogenic gene therapy. Mol Ther Nucleic Acids. 2019;16:38–50.
Askou AL, Benckendorff JNE, Holmgaard A, Storm T, Aagaard L, Bek T, et al. Suppression of choroidal neovascularization in mice by subretinal delivery of multigenic lentiviral vectors encoding anti-angiogenic MicroRNAs. Hum Gene Ther Methods. 2017;28:222–33.
Davidsohn N, Pezzone M, Vernet A, Graveline A, Oliver D, Slomovic S, et al. A single combination gene therapy treats multiple age-related diseases. Proc Natl Acad Sci USA. 2019;116:23505–11.
Jolly JK, Bridge H, MacLaren RE. Outcome measures used in ocular gene therapy trials: a scoping review of current practice. Front Pharmacol. 2019;10:1076.
Lahteenvuo J, Yla-Herttuala S. Advances and challenges in cardiovascular gene therapy. Hum Gene Ther. 2017;28:1024–32.
Hasler PW, Bloch SB, Villumsen J, Fuchs J, Lund-Andersen H, Larsen M. Safety study of 38,503 intravitreal ranibizumab injections performed mainly by physicians in training and nurses in a hospital setting. Acta Ophthalmol. 2015;93:122–5.
White W. A rare disease patient/caregiver perspective on fair pricing and access to gene-based therapies. Gene Ther. 2019. https://doi.org/10.1038/s41434-019-0110-7.
Duncan JL, Pierce EA, Laster AM, Daiger SP, Birch DG, Ash JD, et al. Inherited retinal degenerations: current landscape and knowledge gaps. Transl Vis Sci Technol. 2018;7:6.
Acknowledgements
This work was supported by the Faculty of Health Sciences, the Danish Eye Research Foundation (TJC), Aase and Ejnar Danielsen’s Foundation (TJC), and the Velux Foundation (ALA).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Askou, A.L., Jakobsen, T.S. & Corydon, T.J. Retinal gene therapy: an eye-opener of the 21st century. Gene Ther 28, 209–216 (2021). https://doi.org/10.1038/s41434-020-0168-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41434-020-0168-2
This article is cited by
-
Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration
Journal of Neuroinflammation (2021)