AAV2 vector optimization for retinal ganglion cell-targeted delivery of therapeutic genes.
Journal
Gene therapy
ISSN: 1476-5462
Titre abrégé: Gene Ther
Pays: England
ID NLM: 9421525
Informations de publication
Date de publication:
Mar 2024
Mar 2024
Historique:
received:
29
09
2023
accepted:
19
12
2023
revised:
12
12
2023
medline:
18
3
2024
pubmed:
11
1
2024
entrez:
10
1
2024
Statut:
ppublish
Résumé
Recombinant adeno-associated virus (AAV)-2 has significant potential as a delivery vehicle of therapeutic genes to retinal ganglion cells (RGCs), which are key interventional targets in optic neuropathies. Here we show that when injected intravitreally, AAV2 engineered with a reporter gene driven by cytomegalovirus (CMV) enhancer and chicken β-actin (CBA) promoters, displays ubiquitous and high RGC expression, similar to its synthetic derivative AAV8BP2. A novel AAV2 vector combining the promoter of the human RGC-selective γ-synuclein (hSNCG) gene and woodchuck hepatitis post-transcriptional regulatory element (WPRE) inserted upstream and downstream of a reporter gene, respectively, induces widespread transduction and strong transgene expression in RGCs. High transduction efficiency and selectivity to RGCs is further achieved by incorporating in the vector backbone a leading CMV enhancer and an SV40 intron at the 5' and 3' ends, respectively, of the reporter gene. As a delivery vehicle of hSIRT1, a 2.2-kb therapeutic gene with anti-apoptotic, anti-inflammatory and anti-oxidative stress properties, this recombinant vector displayed improved transduction efficiency, a strong, widespread and selective RGC expression of hSIRT1, and increased RGC survival following optic nerve crush. Thus, AAV2 vector carrying hSNCG promoter with additional regulatory sequences may offer strong potential for enhanced effects of candidate gene therapies targeting RGCs.
Identifiants
pubmed: 38200264
doi: 10.1038/s41434-023-00436-8
pii: 10.1038/s41434-023-00436-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
175-186Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)
ID : EY019014
Organisme : U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)
ID : EY030163
Organisme : Robert Wood Johnson Foundation (RWJF)
ID : Harold Amos Faculty Development Award
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Wong KA, Benowitz LI. Retinal ganglion cell survival and axon regeneration after optic nerve injury: role of inflammation and other factors. Int J Mol Sci. 2022;23:10179.
pubmed: 36077577
pmcid: 9456227
doi: 10.3390/ijms231710179
Sanz-Morello B, Ahmadi H, Vohra R, Saruhanian S, Freude KK, Hamann S, et al. Oxidative stress in optic neuropathies. Antioxidants. 2021;10:1538.
pubmed: 34679672
pmcid: 8532958
doi: 10.3390/antiox10101538
Newman NJ, Yu-Wai-Man P, Biousse V, Carelli V. Understanding the molecular basis and pathogenesis of hereditary optic neuropathies: towards improved diagnosis and management. Lancet Neurol. 2023;22:172–88.
pubmed: 36155660
doi: 10.1016/S1474-4422(22)00174-0
Quigley HA. Glaucoma. Lancet. 2011;377:1367–77.
pubmed: 21453963
doi: 10.1016/S0140-6736(10)61423-7
Shu DY, Chaudhary S, Cho KS, Lennikov A, Miller WP, Thorn DC, et al. Role of oxidative stress in ocular diseases: a balancing act. Metabolites. 2023;13:187.
pubmed: 36837806
pmcid: 9960073
doi: 10.3390/metabo13020187
Fague L, Liu YA, Marsh-Armstrong N. The basic science of optic nerve regeneration. Ann Transl Med. 2021;9:1276.
pubmed: 34532413
pmcid: 8421956
doi: 10.21037/atm-20-5351
Levin LA, Patrick C, Choudry NB, Sharif NA, Goldberg JL. Neuroprotection in neurodegenerations of the brain and eye: lessons from the past and directions for the future. Front Neurol. 2022;13:964197.
pubmed: 36034312
pmcid: 9412944
doi: 10.3389/fneur.2022.964197
Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019;18:358–78.
pubmed: 30710128
pmcid: 6927556
doi: 10.1038/s41573-019-0012-9
Zinn E, Vandenberghe LH. Adeno-associated virus: fit to serve. Curr Opin Virol. 2014;8:90–7.
pubmed: 25128609
doi: 10.1016/j.coviro.2014.07.008
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;337:193–206.
pubmed: 24702846
doi: 10.1016/j.crvi.2013.11.011
Martin KR, Quigley HA. Gene therapy for optic nerve disease. Eye. 2004;18:1049–55.
pubmed: 15534589
doi: 10.1038/sj.eye.6701579
Mak KY, Rajapaksha IG, Angus PW, Herath CB. The adeno-associated virus - a safe and promising vehicle for liverspecific gene therapy of inherited and non-inherited disorders. Curr Gene Ther. 2017;17:4–16.
pubmed: 28292253
doi: 10.2174/1566523217666170314141931
Bennett J. Taking stock of retinal gene therapy: looking back and moving forward. Mol Ther. 2017;25:1076–94.
pubmed: 28391961
pmcid: 5417792
doi: 10.1016/j.ymthe.2017.03.008
Gao J, Hussain RM, Weng CY. Voretigene neparvovec in retinal diseases: a review of the current clinical evidence. Clin Ophthalmol. 2020;14:3855–69.
pubmed: 33223822
pmcid: 7671481
doi: 10.2147/OPTH.S231804
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.
pubmed: 28712537
pmcid: 5726391
doi: 10.1016/S0140-6736(17)31868-8
Buning H, Perabo L, Coutelle O, Quadt-Humme S, Hallek M. Recent developments in adeno-associated virus vector technology. J Gene Med. 2008;10:717–33.
pubmed: 18452237
doi: 10.1002/jgm.1205
Srivastava A. In vivo tissue-tropism of adeno-associated viral vectors. Curr Opin Virol. 2016;21:75–80.
pubmed: 27596608
pmcid: 5138125
doi: 10.1016/j.coviro.2016.08.003
O’Donnell J, Taylor KA, Chapman MS. Adeno-associated virus-2 and its primary cellular receptor–Cryo-EM structure of a heparin complex. Virology. 2009;385:434–43.
pubmed: 19144372
doi: 10.1016/j.virol.2008.11.037
Hadaczek P, Mirek H, Bringas J, Cunningham J, Bankiewicz K. Basic fibroblast growth factor enhances transduction, distribution, and axonal transport of adeno-associated virus type 2 vector in rat brain. Hum Gene Ther. 2004;15:469–79.
pubmed: 15144577
doi: 10.1089/10430340460745793
Kashiwakura Y, Tamayose K, Iwabuchi K, Hirai Y, Shimada T, Matsumoto K, et al. Hepatocyte growth factor receptor is a coreceptor for adeno-associated virus type 2 infection. J Virol. 2005;79:609–14.
pubmed: 15596854
pmcid: 538679
doi: 10.1128/JVI.79.1.609-614.2005
Asokan A, Hamra JB, Govindasamy L, Agbandje-McKenna M, Samulski RJ. Adeno-associated virus type 2 contains an integrin alpha5beta1 binding domain essential for viral cell entry. J Virol. 2006;80:8961–9.
pubmed: 16940508
pmcid: 1563945
doi: 10.1128/JVI.00843-06
Kurzeder C, Koppold B, Sauer G, Pabst S, Kreienberg R, Deissler H. CD9 promotes adeno-associated virus type 2 infection of mammary carcinoma cells with low cell surface expression of heparan sulphate proteoglycans. Int J Mol Med. 2007;19:325–33.
pubmed: 17203208
Van Vliet KM, Blouin V, Brument N, Agbandje-McKenna M, Snyder RO. The role of the adeno-associated virus capsid in gene transfer. Methods Mol Biol. 2008;437:51–91.
pubmed: 18369962
pmcid: 7120696
doi: 10.1007/978-1-59745-210-6_2
Rabinowitz JE, Rolling F, Li C, Conrath H, Xiao W, Xiao X, et al. Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol. 2002;76:791–801.
pubmed: 11752169
pmcid: 136844
doi: 10.1128/JVI.76.2.791-801.2002
Ramachandran PS, Lee V, Wei Z, Song JY, Casal G, Cronin T, et al. Evaluation of dose and safety of AAV7m8 and AAV8BP2 in the non-human primate retina. Hum Gene Ther. 2017;28:154–67.
pubmed: 27750461
pmcid: 5312498
doi: 10.1089/hum.2016.111
Ross AG, Chaqour B, McDougald DS, Dine KE, Duong TT, Shindler RE, et al. Selective upregulation of sirt1 expression in retinal ganglion cells by AAV-mediated gene delivery increases neuronal cell survival and alleviates axon demyelination associated with optic neuritis. Biomolecules. 2022;12:830.
pubmed: 35740955
pmcid: 9221096
doi: 10.3390/biom12060830
Yue J, Khan RS, Duong TT, Dine KE, Cui QN, O’Neill N, et al. Cell-specific expression of human sirt1 by gene therapy reduces retinal ganglion cell loss induced by elevated intraocular pressure. Neurotherapeutics. 2023;20:896–907.
pubmed: 36941497
doi: 10.1007/s13311-023-01364-6
McDougald DS, Dine KE, Zezulin AU, Bennett J, Shindler KS. SIRT1 and NRF2 gene transfer mediate distinct neuroprotective effects upon retinal ganglion cell survival and function in experimental optic neuritis. Invest Ophthalmol Vis Sci. 2018;59:1212–20.
pubmed: 29494741
pmcid: 5839257
doi: 10.1167/iovs.17-22972
Alam F, Syed H, Amjad S, Baig M, Khan TA, Rehman R. Interplay between oxidative stress, SIRT1, reproductive and metabolic functions. Curr Res Physiol. 2021;4:119–24.
pubmed: 34746831
pmcid: 8562188
doi: 10.1016/j.crphys.2021.03.002
Singh V, Ubaid S. Role of silent information regulator 1 (SIRT1) in regulating oxidative stress and inflammation. Inflammation. 2020;43:1589–98.
pubmed: 32410071
doi: 10.1007/s10753-020-01242-9
Li L, Zhi D, Cheng R, Li J, Luo C, Li H. The neuroprotective role of SIRT1/PGC-1alpha signaling in limb postconditioning in cerebral ischemia/reperfusion injury. Neurosci Lett. 2021;749:135736.
pubmed: 33600904
doi: 10.1016/j.neulet.2021.135736
Nita M, Grzybowski A. Interplay between reactive oxygen species and autophagy in the course of age-related macular degeneration. EXCLI J. 2020;19:1353–71.
pubmed: 33192217
pmcid: 7658465
Samarin J, Wessel J, Cicha I, Kroening S, Warnecke C, Goppelt-Struebe M. FoxO proteins mediate hypoxic induction of connective tissue growth factor in endothelial cells. J Biol Chem. 2010;285:4328–36.
pubmed: 20018872
doi: 10.1074/jbc.M109.049650
Chaffiol A, Caplette R, Jaillard C, Brazhnikova E, Desrosiers M, Dubus E, et al. A new promoter allows optogenetic vision restoration with enhanced sensitivity in macaque retina. Mol Ther. 2017;25:2546–60.
pubmed: 28807567
pmcid: 5675708
doi: 10.1016/j.ymthe.2017.07.011
Bennicelli J, Wright JF, Komaromy A, Jacobs JB, Hauck B, Zelenaia O, et al. Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther. 2008;16:458–65.
pubmed: 18209734
doi: 10.1038/sj.mt.6300389
Ross AG, McDougald DS, Khan RS, Duong TT, Dine KE, Aravand P, et al. Rescue of retinal ganglion cells in optic nerve injury using cell-selective AAV mediated delivery of SIRT1. Gene Ther. 2021;28:256–64.
pubmed: 33589779
pmcid: 8149296
doi: 10.1038/s41434-021-00219-z
Zuo L, Khan RS, Lee V, Dine K, Wu W, Shindler KS. SIRT1 promotes RGC survival and delays loss of function following optic nerve crush. Invest Ophthalmol Vis Sci. 2013;54:5097–102.
pubmed: 23821198
pmcid: 3726244
doi: 10.1167/iovs.13-12157
Cronin T, Vandenberghe LH, Hantz P, Juttner J, Reimann A, Kacso AE, et al. Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno-associated virus capsid and promoter. EMBO Mol Med. 2014;6:1175–90.
pubmed: 25092770
pmcid: 4197864
doi: 10.15252/emmm.201404077
Xu L, Daly T, Gao C, Flotte TR, Song S, Byrne BJ, et al. CMV-beta-actin promoter directs higher expression from an adeno-associated viral vector in the liver than the cytomegalovirus or elongation factor 1 alpha promoter and results in therapeutic levels of human factor X in mice. Hum Gene Ther. 2001;12:563–73.
pubmed: 11268288
doi: 10.1089/104303401300042500
Boye SE, Alexander JJ, Witherspoon CD, Boye SL, Peterson JJ, Clark ME, et al. Highly efficient delivery of adeno-associated viral vectors to the primate retina. Hum Gene Ther. 2016;27:580–97.
pubmed: 27439313
pmcid: 4991591
doi: 10.1089/hum.2016.085
Loeb JE, Cordier WS, Harris ME, Weitzman MD, Hope TJ. Enhanced expression of transgenes from adeno-associated virus vectors with the woodchuck hepatitis virus posttranscriptional regulatory element: implications for gene therapy. Hum Gene Ther. 1999;10:2295–305.
pubmed: 10515449
doi: 10.1089/10430349950016942
Popa I, Harris ME, Donello JE, Hope TJ. CRM1-dependent function of a cis-acting RNA export element. Mol Cell Biol. 2002;22:2057–67.
pubmed: 11884594
pmcid: 133666
doi: 10.1128/MCB.22.7.2057-2067.2002
Graveley BR, Hertel KJ, Maniatis T. The role of U2AF35 and U2AF65 in enhancer-dependent splicing. RNA. 2001;7:806–18.
pubmed: 11421359
pmcid: 1370132
doi: 10.1017/S1355838201010317
Xu DH, Wang XY, Jia YL, Wang TY, Tian ZW, Feng X, et al. SV40 intron, a potent strong intron element that effectively increases transgene expression in transfected Chinese hamster ovary cells. J Cell Mol Med. 2018;22:2231–9.
pubmed: 29441681
pmcid: 5867124
doi: 10.1111/jcmm.13504
Rotondaro L, Mele A, Rovera G. Efficiency of different viral promoters in directing gene expression in mammalian cells: effect of 3’-untranslated sequences. Gene. 1996;168:195–8.
pubmed: 8654943
doi: 10.1016/0378-1119(95)00767-9
Xu ZL, Mizuguchi H, Ishii-Watabe A, Uchida E, Mayumi T, Hayakawa T. Optimization of transcriptional regulatory elements for constructing plasmid vectors. Gene. 2001;272:149–56.
pubmed: 11470520
doi: 10.1016/S0378-1119(01)00550-9
Hermonat PL, Quirk JG, Bishop BM, Han L. The packaging capacity of adeno-associated virus (AAV) and the potential for wild-type-plus AAV gene therapy vectors. FEBS Lett. 1997;407:78–84.
pubmed: 9141485
doi: 10.1016/S0014-5793(97)00311-6
Tenenbaum L, Chtarto A, Lehtonen E, Velu T, Brotchi J, Levivier M. Recombinant AAV-mediated gene delivery to the central nervous system. J Gene Med. 2004;6:S212–22.
pubmed: 14978764
doi: 10.1002/jgm.506
Prosch S, Stein J, Staak K, Liebenthal C, Volk HD, Kruger DH. Inactivation of the very strong HCMV immediate early promoter by DNA CpG methylation in vitro. Biol Chem Hoppe Seyler. 1996;377:195–201.
pubmed: 8722321
doi: 10.1515/bchm3.1996.377.3.195
Chintalapudi SR, Morales-Tirado VM, Williams RW, Jablonski MM. Multipronged approach to identify and validate a novel upstream regulator of Sncg in mouse retinal ganglion cells. FEBS J. 2016;283:678–93.
pubmed: 26663874
doi: 10.1111/febs.13620
Claes M, Moons L. Retinal ganglion cells: global number, density and vulnerability to glaucomatous injury in common laboratory mice. Cells. 2022;11:2689.
pubmed: 36078097
pmcid: 9454702
doi: 10.3390/cells11172689
Rodriguez AR, de Sevilla Muller LP, Brecha NC. The RNA binding protein RBPMS is a selective marker of ganglion cells in the mammalian retina. J Comp Neurol. 2014;522:1411–43.
pubmed: 24318667
pmcid: 3959221
doi: 10.1002/cne.23521
Wang Q, Zhuang P, Huang H, Li L, Liu L, Webber HC, et al. Mouse gamma-synuclein promoter-mediated gene expression and editing in mammalian retinal ganglion cells. J Neurosci. 2020;40:3896–914.
pubmed: 32300046
pmcid: 7219295
doi: 10.1523/JNEUROSCI.0102-20.2020
Ge J, Jin L, Tang X, Gao D, An Q, Ping W. Optimization of eGFP expression using a modified baculovirus expression system. J Biotechnol. 2014;173:41–6.
pubmed: 24445173
doi: 10.1016/j.jbiotec.2014.01.003
Martin KR, Quigley HA, Zack DJ, Levkovitch-Verbin H, Kielczewski J, Valenta D, et al. Gene therapy with brain-derived neurotrophic factor as a protection: retinal ganglion cells in a rat glaucoma model. Invest Ophthalmol Vis Sci. 2003;44:4357–65.
pubmed: 14507880
doi: 10.1167/iovs.02-1332
Powell SK, Rivera-Soto R, Gray SJ. Viral expression cassette elements to enhance transgene target specificity and expression in gene therapy. Discov Med. 2015;19:49–57.
pubmed: 25636961
pmcid: 4505817
Wang L, Wang Z, Zhang F, Zhu R, Bi J, Wu J, et al. Enhancing transgene expression from recombinant AAV8 vectors in different tissues using woodchuck hepatitis virus post-transcriptional regulatory element. Int J Med Sci. 2016;13:286–91.
pubmed: 27076785
pmcid: 4829541
doi: 10.7150/ijms.14152
Gruh I, Wunderlich S, Winkler M, Schwanke K, Heinke J, Blomer U, et al. Human CMV immediate-early enhancer: a useful tool to enhance cell-type-specific expression from lentiviral vectors. J Gene Med. 2008;10:21–32.
pubmed: 18022932
doi: 10.1002/jgm.1122
Ghazal P, Lubon H, Hennighausen L. Multiple sequence-specific transcription factors modulate cytomegalovirus enhancer activity in vitro. Mol Cell Biol. 1988;8:1809–11.
pubmed: 2837656
pmcid: 363343
Le Hir H, Nott A, Moore MJ. How introns influence and enhance eukaryotic gene expression. Trends Biochem Sci. 2003;28:215–20.
pubmed: 12713906
doi: 10.1016/S0968-0004(03)00052-5
Huang MT, Gorman CM. Intervening sequences increase efficiency of RNA 3’ processing and accumulation of cytoplasmic RNA. Nucleic Acids Res. 1990;18:937–47.
pubmed: 1690394
pmcid: 330348
doi: 10.1093/nar/18.4.937
Fonseca-Kelly Z, Nassrallah M, Uribe J, Khan RS, Dine K, Dutt M, et al. Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis. Front Neurol. 2012;3:84.
pubmed: 22654783
pmcid: 3359579
doi: 10.3389/fneur.2012.00084
Shindler KS, Ventura E, Rex TS, Elliott P, Rostami A. SIRT1 activation confers neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci. 2007;48:3602–9.
pubmed: 17652729
doi: 10.1167/iovs.07-0131