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Controlling AAV Tropism in the Nervous System with Natural and Engineered Capsids
Open accessAbstract
More than one hundred naturally occurring variants of adeno-associated virus (AAV) have been identified, and this library has been further expanded by an array of techniques for modification of the viral capsid. AAV capsid variants possess unique antigenic profiles and demonstrate distinct cellular tropisms driven by differences in receptor binding. AAV capsids can be chemically modified to alter tropism, can be produced as hybrid vectors that combine the properties of multiple serotypes, and can carry peptide insertions that introduce novel receptor-binding activity. Furthermore, directed evolution of shuffled genome libraries can identify engineered variants with unique properties, and rational modification of the viral capsid can alter tropism, reduce blockage by neutralizing antibodies, or enhance transduction efficiency. This large number of AAV variants and engineered capsids provides a varied toolkit for gene delivery to the CNS and retina, with specialized vectors available for many applications, but selecting a capsid variant from the array of available vectors can be difficult. This chapter describes the unique properties of a range of AAV variants and engineered capsids, and provides a guide for selecting the appropriate vector for specific applications in the CNS and retina.
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“With translational studies in mind, it is important to demonstrate consistent tropism of a particular rAAV, as examples where the tropism of a given rAAV capsid does not remain consistent in rodents and higher animals have been described [7].”
From Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates (2017) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“we performed co-labeling via IHC and confirmed the results of previous studies (Castle et al., 2016; Hudry et al., 2016; Schuster et al., 2014; Aschauer et al., 2013; Hinderer et al., 2014; Samaranch et al., 2012), showing that AAV9, when injected directly into the adult brain parenchyma, is not expressed in microglia and minimally expressed in astrocytes (Figure S5).”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Castle et al., 2016
Experimental — accuracy not yet measuredIn the citing paper
“RPE cells can be targeted using AAV1, AAV4, or AAV6 vectors or with the engineered AAV2-7m8 vector, and photoreceptors and Müller glial cells are targeted by serotypes AAV2, AAV5, AAV6, AAV7, AAV8, and AAV9 as well as engineered AAV2-7m8 and AAV8BP2 vectors.56,112–116”
From Gene Therapy for Retinal Degenerative Diseases: Progress, Challenges, and Future Directions (2023) · cites this paper as [112]
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Citations
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Targeting photoreceptors via intravitreal delivery using novel, capsid-mutated AAV vectors
Kay, C. N., Ryals, R. C., Aslanidi, G. V., Min, S. H., Ruan, Q., Sun, J., Dyka, F. M., Kasuga, D., Ayala, A. E., Van Vliet, K., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0062097 · Cited by 168 · cited 1×
“Indeed, mutating several surface exposed tyrosine and threonine residues signifi cantly increased the transduction effi ciency of AAVs 2, 5, and 8 [ 111 , 112 ].”
BackgroundKoprich, J. B., Johnston, T. H., Reyes, M. G., Sun, X., & Brotchie, J. M. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-43 · Cited by 168 · cited 1×
“Further, AAV1/2 appears to combine the tropism of AAV2 for TH-positive dopamine neurons with the ability of AAV1 to diffuse more widely through brain tissue, mediating strong transduction of dopamine neurons in the substantia nigra, and has been used to model Parkinson’s disease in the rat [70].”
MethodShi, W., Arnold, G. S., & Bartlett, J. S. (2001) · Human Gene Therapy · doi:10.1089/104303401750476212 · Cited by 167
Castle, M. J., Gershenson, Z. T., Giles, A. R., Holzbaur, E. L. F., & Wolfe, J. H. N. (2014) · Human Gene Therapy · doi:10.1089/hum.2013.189 · Cited by 165 · cited 2×
“Within the brain, AAV9 is most frequently observed to undergo axonal transport, and is the recommended choice if distal transduction is desired [21, 23, 34, 36, 57, 60].”
BackgroundSelf-citationShi, W., & Bartlett, J. S. (2003) · Molecular Therapy · doi:10.1016/s1525-0016(03)00042-x · Cited by 164 · cited 1×
“To date, improved targeting of skeletal muscle [81, 82], cardiac muscle [83], vasculature [84– 86], lung [87, 88], diseased brain endothelial cells [89], retina [90], ovarian cancer cells [91] and breast cancer cells [88] has been reported.”
BackgroundQiao, C., Yuan, Z., Li, J., He, B., Zheng, H., Mayer, C., Li, J., & Xiao, X. (2011) · Gene Therapy · doi:10.1038/gt.2010.157 · Cited by 163
Molecular Engineering of Viral Gene Delivery Vehicles
Schaffer, D. V., Koerber, J. T., & Lim, K. (2008) · Annual Review of Biomedical Engineering · doi:10.1146/annurev.bioeng.10.061807.160514 · Cited by 162 · cited 1×
“[ 61 , 62 ]).”
Lawlor, P. A., Bland, R. J., Mouravlev, A., Young, D., & During, M. J. (2009) · Molecular Therapy · doi:10.1038/mt.2009.170 · Cited by 161 · cited 20×
“In nonhuman primate subretinal injections, AAV8 efficiently targets rod PRs [54], while AAV9 is superior for cone PRs and retains tropism for rod PRs [53].”
BackgroundInfluentialGeneration and characterization of chimeric recombinant AAV vectors
Hauck, B., Chen, L., & Xiao, W. (2003) · Molecular Therapy · doi:10.1016/s1525-0016(03)00012-1 · Cited by 160 · cited 1×
“Hybrid capsids of AAV1 and AAV2 (AAV1/2) can mediate stronger transgene expression in lung and muscle in vivo than either of the parental serotypes alone [69].”
BackgroundSamaranch, L., Salegio, E. A., Sebastián, W. S., Kells, A. P., Bringas, J. R., Forsayeth, J., & Bankiewicz, K. S. (2013) · Human Gene Therapy · doi:10.1089/hum.2013.005 · Cited by 158 · cited 1×
“In contrast, AAV7 and AAV9 can bypass the ependymal layer following intrathecal injection, penetrating the parenchyma and transducing neurons throughout the cortex, cerebellum, and spinal cord [37, 38].”
BackgroundComparison of Adeno-Associated Viral Vector Serotypes for Spinal Cord and Motor Neuron Gene Delivery
Snyder, B. R., Gray, S. J., Quach, E. T., Huang, J. W., Leung, C. H., Samulski, R. J., Boulis, N. M., & Federici, T. (2011) · Human Gene Therapy · doi:10.1089/hum.2011.008 · Cited by 156 · cited 5×
“Thus, CSF injection of AAV4 can mediate transduction of epithelial cells, CSF injection of AAV7 or 9 can mediate widespread transduction of cortical, cerebellar, and spinal neurons, CSF injection of AAV6 can mediate transduction of spinal motor neurons, and CSF injection of AAV8 can mediate transduction of large-diame…”
BackgroundInfluentialKügler, S., Lingor, P., Schöll, U., Zolotukhin, S., & Bähr, M. (2003) · Virology · doi:10.1016/s0042-6822(03)00162-4 · Cited by 155 · cited 1×
“8 kb neuron-specifi c enolase promoter [ 121 ], the 470 bp human synapsin-1 promoter [ 120 , 122 ], the 229 bp MeCP2 promoter [ 123 ], and the 2 kb herpes simplex virus 1 latency associated transcript promoter [ 124 ] can all drive neuron-specifi c gene expression.”
BackgroundHoward, D. B., Powers, K., Wang, Y., & Harvey, B. K. (2008) · Virology · doi:10.1016/j.virol.2007.10.007 · Cited by 149 · cited 1×
“AAV serotypes 1, 2, 6, 7, 8, and 9 transduce both neurons and astrocytes in primary culture [16, 17].”
BackgroundSchambach, A., Bohne, J., Baum, C., Hermann, F. G., Egerer, L., von Laer, D., & Giroglou, T. (2005) · Gene Therapy · doi:10.1038/sj.gt.3302698 · Cited by 145
Towne, C. L., Raoul, C., Schneider, B. L., & Aebischer, P. (2008) · Molecular Therapy · doi:10.1038/mt.2008.73 · Cited by 137
Erratum: Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2
Girod, A., Ried, M. U., Wobus, C., Lahm, H., Leike, K., Kleinschmidt, J., Deléage, G., & Hallek, M. J. (1999) · Nature Medicine · doi:10.1038/71021 · Cited by 136
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Glial promoter selectivity following AAV-delivery to the immature brain
von Jonquieres, G., Mersmann, N., Klugmann, C. B., Harasta, A. E., Lutz, B., Teahan, O., Housley, G. D., Fröhlich, D., Krämer-Albers, E.-M., & Klugmann, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065646 · Cited by 133
Ponnazhagan, S., Mahendra, G., Kumar, S., Thompson, J. A., & Castillas, M. (2002) · Journal of Virology · doi:10.1128/jvi.76.24.12900-12907.2002 · Cited by 129 · cited 1×
“ip1 cells more than 100-fold [ 64 ].”
Yang, Q., Mamounas, M. J., Yu, G., Kennedy, S. P., Leaker, B. R., Merson, J. R., Wong‐Staal, F., Yu, M., & Barber, J. R. (1998) · Human Gene Therapy · doi:10.1089/hum.1998.9.13-1929 · Cited by 127 · cited 1×
“The earliest successful alterations of AAV tropism by capsid engineering relied on insertion of short peptides into the AAV capsid [72].”
BackgroundEfficient Retrograde Neuronal Transduction Utilizing Self-complementary AAV1
Hollis, E. R., II, Kadoya, K., Hirsch, M. L., Samulski, R. J., & Tuszynski, M. H. (2008) · Molecular Therapy · doi:10.1038/sj.mt.6300367 · Cited by 126 · cited 2×
“AAV1 appears to be more effective than AAVs 2, 3, 4, 5, or 6 for retrograde transduction of motor neurons following muscle or sciatic nerve injection [56].”
BackgroundReimsnider, S., Manfredsson, F. P., Muzyczka, N., & Mandel, R. J. (2007) · Molecular Therapy · doi:10.1038/sj.mt.6300227 · Cited by 125 · cited 1×
“AAV2 diffuses less readily through both the brain and spinal cord parenchyma when compared against other serotypes, and therefore mediates transduction over a smaller area [19, 28, 32, 33].”
BackgroundVascular bed-targeted in vivo gene delivery using tropism-modified adeno-associated viruses
Work, L. M., Büning, H., Ela Hunt, B., Nicklin, S. A., Denby, L., Britton, N., Leike, K., Odenthal, M., Drebber, U., Hallek, M. J., et al. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2005.11.013 · Cited by 124
Asuri, P., Bartel, M. A., Vazin, T., Jang, J.-H., Wong, T. B., & Schaffer, D. V. (2012) · Molecular Therapy · doi:10.1038/mt.2011.255 · Cited by 119 · cited 1×
“Capsids with improved transduction of heart [ 95 ], lung [ 96 , 97 ], Müller glia in the retina [ 98 ], CNS [ 99 – 101 ], and neural and pluripotent stem cells [ 102 , 103 ] have been described, with numerous others yet unpublished.”
BackgroundBuilding a Better Vector: The Manipulation of AAV Virions
Rabinowitz, J. E., & Samulski, R. J. (2000) · Virology · doi:10.1006/viro.2000.0707 · Cited by 118 · cited 1×
“Hybrid capsids are designed to harness the structural similarity among AAVs, combining beneficial properties from two or more different serotypes by co-expressing their capsid proteins during vector production [68].”
BackgroundBoye, S. E., Alexander, J. J., Boye, S. L., Witherspoon, C. D., Sandefer, K. J., Conlon, T. J., Erger, K., Sun, J., Ryals, R., Chiodo, V. A., et al. (2012) · Human Gene Therapy · doi:10.1089/hum.2012.125 · Cited by 117 · cited 1×
“shown to target both rod and cone PRs, but has not been compared directly in this setting against other serotypes [55].”
ResultAdeno-associated virus vector-mediated transduction in the cat brain
Vite, C. H., Passini, M. A., Haskins, M. E., & Wolfe, J. H. N. (2003) · Gene Therapy · doi:10.1038/sj.gt.3302087 · Cited by 110
Self-citationJang, J., Koerber, J. T., Kim, J., Asuri, P., Vazin, T., Bartel, M. A., Keung, A. J., Kwon, I., Park, K. I., & Schaffer, D. V. (2011) · Molecular Therapy · doi:10.1038/mt.2010.287 · Cited by 101
Castle, M. J., Perlson, E., Holzbaur, E. L. F., & Wolfe, J. H. N. (2013) · Molecular Therapy · doi:10.1038/mt.2013.237 · Cited by 98 · cited 1×
“Axonal transport is a fundamental property of AAV vectors, and thus any vector that is endocytosed at high levels by projection neurons is likely to transduce distal brain regions [57, 58].”
BackgroundSelf-citationAAV9 targets cone photoreceptors in the nonhuman primate retina
Vandenberghe, L. H., Bell, P., Maguire, A. M., Xiao, R., Hopkins, T. B., Grant, R., Bennett, J., & Wilson, J. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053463 · Cited by 97 · cited 7×
“In nonhuman primate subretinal injections, AAV8 efficiently targets rod PRs [54], while AAV9 is superior for cone PRs and retains tropism for rod PRs [53].”
BackgroundInfluentialSelf-citationLi, C., Diprimio, N., Bowles, D. E., Hirsch, M. L., Monahan, P. E., Asokan, A., Rabinowitz, J., Agbandje-McKenna, M., & Samulski, R. J. (2012) · Journal of Virology · doi:10.1128/jvi.00675-12 · Cited by 96
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A muscle-targeting peptide displayed on AAV2 improves muscle tropism on systemic delivery
Yu, C.-Y., Yuan, Z., Cao, Z., Wang, B., Qiao, C., Li, J., & Xiao, X. (2009) · Gene Therapy · doi:10.1038/gt.2009.59 · Cited by 90 · cited 1×
“To date, improved targeting of skeletal muscle [81, 82], cardiac muscle [83], vasculature [84– 86], lung [87, 88], diseased brain endothelial cells [89], retina [90], ovarian cancer cells [91] and breast cancer cells [88] has been reported.”
BackgroundLi, W., Zhang, L., Johnson, J. S., Wu, Z., Grieger, J. C., Xiao, P., Drouin, L. M., Agbandje‐McKenna, M., Pickles, R. J., & Samulski, R. J. (2009) · Molecular Therapy · doi:10.1038/mt.2009.155 · Cited by 89 · cited 1×
“Capsids with improved transduction of heart [95], lung [96, 97], Müller glia in the retina [98], CNS [99–101], and neural and pluripotent stem cells [102, 103] have been described, with numerous others yet unpublished.”
BackgroundRoyo, N. C., Vandenberghe, L. H., Ma, J.-Y., Hauspurg, A. K., Yu, L., Maronski, M., Johnston, J., Dichter, M. A., Wilson, J. M., & Watson, D. J. (2007) · Brain Research · doi:10.1016/j.brainres.2007.11.015 · Cited by 86 · cited 3×
“AAV9, however, has relatively weak neuronal tropism in vitro, with less than 50 % of transduced cells representing neurons [17].”
BackgroundSelf-citationKingsman, S. M., Mitrophanous, K., & Olsen, J. C. (2005) · Gene Therapy · doi:10.1038/sj.gt.3302417 · Cited by 84 · cited 1×
“WPREs have also been implicated as a contributing or causal factor in oncogenesis in preclinical studies, likely via an ORF within the WPRE [ 127 ].”
BackgroundLiu, G., Martins, I. H., Chiorini, J. A., & Davidson, B. L. (2005) · Gene Therapy · doi:10.1038/sj.gt.3302554 · Cited by 84 · cited 1×
“AAV4 possesses strong glial tropism in vivo, and primarily drives gene expression within glial fibrillary acidic protein (GFAP)-positive astrocytes [25].”
BackgroundUtility of PEGylated recombinant adeno-associated viruses for gene transfer
Le, H. T., Yu, Q.-C., Wilson, J. M., & Croyle, M. A. (2005) · Journal of Controlled Release · doi:10.1016/j.jconrel.2005.07.019 · Cited by 82 · cited 1×
“Indeed, moderate success has been achieved by coating capsids with poly(ethylene) glycol [65], poly-[N-(2-hydroxypropyl) methacrylamide] [66], and α-dicarbonyl compounds [67].”
BackgroundAltering AAV tropism with mosaic viral capsids
Gigout, L. I., Rebollo, P., Clement, N., Warrington, K. H., Muzyczka, N., Linden, R. M., & Weber, T. (2005) · Molecular Therapy · doi:10.1016/j.ymthe.2005.03.005 · Cited by 79 · cited 1×
“This is an important consideration, as the density of receptor-binding peptides on a capsid can affect its tropism [79].”
BackgroundMichelfelder, S., Kohlschütter, J., Skorupa, A., Pfennings, S., Müller, O. J., Kleinschmidt, J. A., & Trepel, M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005122 · Cited by 75 · cited 1×
“To date, improved targeting of skeletal muscle [81, 82], cardiac muscle [83], vasculature [84– 86], lung [87, 88], diseased brain endothelial cells [89], retina [90], ovarian cancer cells [91] and breast cancer cells [88] has been reported.”
BackgroundStieger, K., Colle, M.-A., Dubreil, L., Mendes-Madeira, A., Weber, M., Meur, G. L., Deschamps, J. Y., Provost, N., Nivard, D., Chérel, Y., et al. (2008) · Molecular Therapy · doi:10.1038/mt.2008.41 · Cited by 75 · cited 1×
“AAV8 also possesses tropism for ganglion cells and cells of the inner nuclear layer [50, 54], and demonstrates greater tropism for PRs than AAV2 [54].”
BackgroundTratschin, J.-D., West, M. H. P., Sandbank, T., et al. (1984) · Molecular and Cellular Biology · doi:10.1128/mcb.4.10.2072-2081.1984 · Cited by 75
Vandenberghe, L. H., Breous, E., Nam, H.-J., Gao, G., Xiao, R., Sandhu, A., Johnston, J., Debyser, Z., Agbandje‐McKenna, M., & Wilson, J. M. (2009) · Gene Therapy · doi:10.1038/gt.2009.101 · Cited by 74 · cited 1×
“2, a novel vector with improved transduction in mouse airways, was generated via targeted single amino acid changes to AAV6 [ 107 , 108 ].”
MethodSelf-citationHutson, T. H., Verhaagen, J., Yáñez‐Muñoz, R. J., & Moon, L. D. F. (2011) · Gene Therapy · doi:10.1038/gt.2011.71 · Cited by 74 · cited 1×
“However, others have observed astroglial transduction with AAVs 1, 2, 5, 6, and 8 [22–24], and AAV8 has also been observed to transduce oligodendrocytes within the cortex [24].”
BackgroundYing, Y., Müller, O. J., Goehringer, C., Leuchs, B., Trepel, M., Katus, H. A., & Kleinschmidt, J. A. (2010) · Gene Therapy · doi:10.1038/gt.2010.44 · Cited by 69
Li, M., Jayandharan, G. R., Li, B., Ling, C., Ma, W., Srivastava, A., & Li, Z. (2010) · Human Gene Therapy · doi:10.1089/hum.2010.005 · Cited by 69
Iida, A., Takino, N., Miyauchi, H., Shimazaki, K., & Muramatsu, S. (2013) · BioMed Research International · doi:10.1155/2013/974819 · Cited by 64 · cited 2×
“Tyrosine mutations of different serotypes also demonstrate improved transduction of mesenchymal stem cells [ 113 ] and the mouse brain [ 117 , 118 ].”
BackgroundCarlisle, R. C., Benjamin, R., Briggs, S. S., Jones, S., McIntosh, J., Gill, D. R., Hyde, S., Nathwani, A. C., Šubr, V., Ulbrich, K., et al. (2008) · The Journal of Gene Medicine · doi:10.1002/jgm.1161 · Cited by 61 · cited 1×
“Indeed, moderate success has been achieved by coating capsids with poly(ethylene) glycol [65], poly-[N-(2-hydroxypropyl) methacrylamide] [66], and α-dicarbonyl compounds [67].”
BackgroundJacques, S. J., Ahmed, Z., Forbes, A., Douglas, M. R., Vigenswara, V., Berry, M., & Logan, A. (2012) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2012.03.002 · Cited by 61 · cited 5×
“AAV8 retains its tropism for large-diameter DRG neurons after intraparenchymal injection [39].”
BackgroundInfluentialMicroRNA-Restricted Transgene Expression in the Retina
Karali, M., Manfredi, A., Puppo, A., Marrocco, E., Gargiulo, A., Allocca, M., Corte, M. D., Rossi, S., Giunti, M., Bacci, M. L., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022166 · Cited by 60 · cited 2×
“However, binding sites for the RPE-specifi c miR-204 can block AAV5-mediated gene expression in RPE cells, resulting in PR-specifi c expression [ 130 ].”
BackgroundJudd, J., Wei, F., Nguyen, P. Q., Tartaglia, L. J., Agbandje‐McKenna, M., Silberg, J. J., & Suh, J. (2012) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2012.46 · Cited by 53 · cited 1×
“Although initial experiments focused on the insertion of small peptides (5–15 amino acids), later studies have shown that insertions of full length proteins, such as GFP or mCherry, can also be tolerated without loss of virus function [78, 80].”
BackgroundDirected evolution of adeno-associated virus for glioma cell transduction
Maguire, C. A., Gianni, D., Meijer, D. H., Shaket, L. A., Wakimoto, H., Rabkin, S. D., Gao, G., & Sena‐Esteves, M. (2009) · Journal of Neuro-Oncology · doi:10.1007/s11060-009-9972-7 · Cited by 52
Michelfelder, S., Varadi, K., Raupp, C., Hunger, A., Körbelin, J., Pahrmann, C., Schrepfer, S., Müller, O. J., Kleinschmidt, J. A., & Trepel, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023101 · Cited by 47 · cited 1×
“To date, improved targeting of skeletal muscle [81, 82], cardiac muscle [83], vasculature [84– 86], lung [87, 88], diseased brain endothelial cells [89], retina [90], ovarian cancer cells [91] and breast cancer cells [88] has been reported.”
BackgroundChen, S., Sanmiguel, J. C., Lock, M. W., McMenamin, D., Draper, C., Limberis, M. P., Kassim, S. H., Somanathan, S., Bell, P. L., Johnston, J., et al. (2013) · Human Gene Therapy Clinical Development · doi:10.1089/humc.2013.082 · Cited by 42
Glycated AAV vectors: chemical redirection of viral tissue tropism
Horowitz, E. D., Weinberg, M. S., & Asokan, A. (2011) · Bioconjugate Chemistry · doi:10.1021/bc100477g · Cited by 40 · cited 1×
“Indeed, moderate success has been achieved by coating capsids with poly(ethylene) glycol [65], poly-[N-(2-hydroxypropyl) methacrylamide] [66], and α-dicarbonyl compounds [67].”
BackgroundEngineering adeno-associated virus 2 vectors for targeted gene delivery to atherosclerotic lesions
White, K., Büning, H., Kritz, A., Janicki, H., McVey, J. H., Perabò, L., Murphy, G., Odenthal, M., Work, L. M., Hallek, M. J., et al. (2007) · Gene Therapy · doi:10.1038/sj.gt.3303077 · Cited by 39 · cited 1×
“To date, improved targeting of skeletal muscle [ 81 , 82 ], cardiac muscle [ 83 ], vasculature [ 84 – 86 ], lung [ 87 , 88 ], diseased brain endothelial cells [ 89 ], retina [ 90 ], ovarian cancer cells [ 91 ] and breast cancer cells [ 88 ] has been reported.”
BackgroundHusain, T., Passini, M. A., Parente, M. K., Fraser, N., & Wolfe, J. H. N. (2009) · Gene Therapy · doi:10.1038/gt.2009.52 · Cited by 38 · cited 1×
“8 kb neuron-specifi c enolase promoter [ 121 ], the 470 bp human synapsin-1 promoter [ 120 , 122 ], the 229 bp MeCP2 promoter [ 123 ], and the 2 kb herpes simplex virus 1 latency associated transcript promoter [ 124 ] can all drive neuron-specifi c gene expression.”
BackgroundSelf-citationKlaw, M. C., Xu, C., & Tom, V. J. (2013) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2013.34 · Cited by 36 · cited 1×
“Further, AAVs 1 and 5 demonstrate greater retrograde transduction of brainstem than AAVs 2, 8, or 9 following injection of the transected spinal cord [59].”
BackgroundReceptors and tropisms of envelope viruses
Morizono, K., & Chen, I. S. Y. (2011) · Current Opinion in Virology · doi:10.1016/j.coviro.2011.05.001 · Cited by 36 · cited 1×
“[ 61 , 62 ]).”
Gene Delivery to the Mouse Brain with Adeno-Associated Virus
Passini, M. A., Watson, D. J., & Wolfe, J. H. N. (2004) · Humana Press eBooks · doi:10.1385/1-59259-650-9:225 · Cited by 33 · cited 1×
“AAV2 diffuses less readily through both the brain and spinal cord parenchyma when compared against other serotypes, and therefore mediates transduction over a smaller area [19, 28, 32, 33].”
BackgroundSelf-citationAdeno-associated virus serotype-9 efficiently transduces the retinal outer plexiform layer.
Lei, B., Zhang, K., Yue, Y., Ghosh, A., & Duan, D. (2009) · PubMed Central · Cited by 24
Li, S., Wang, R., Meng, Q.-H., Li, G.-L., Hu, G.-J., Dou, W., Li, Z., & Zhang, Z. (2006) · Brain Research · doi:10.1016/j.brainres.2006.09.042 · Cited by 22
Efficient gene transfer into neurons in monkey brain by adeno-associated virus 8
Masamizu, Y., Okada, T., Ishibashi, H., Takeda, S., Yuasa, S., & Nakahara, K. (2010) · Neuroreport · doi:10.1097/wnr.0b013e328338ba00 · Cited by 22
Improved Adeno-associated Viral Gene Transfer to Murine Glioma
Zolotukhin, I. (2013) · Journal of Genetic Syndromes & Gene Therapy · doi:10.4172/2157-7412.1000133 · Cited by 17 · cited 1×
“Tyrosine mutations of different serotypes also demonstrate improved transduction of mesenchymal stem cells [ 113 ] and the mouse brain [ 117 , 118 ].”
BackgroundPilz, I. H., Pasquale, G. D., Rzadzinska, A. K., Leppla, S. H., & Chiorini, J. A. (2012) · Virology · doi:10.1016/j.virol.2012.03.004 · Cited by 11 · cited 13×
“In primary cultures of rat nervous cells, AAV5 appears to possess a strong glial tropism, and gene expression rarely colocalizes with the neuronal marker Methods Mol Biol.”
BackgroundInfluentialComparison of AAV2 and AAV5 in gene transfer in the injured spinal cord of mice
Peng, S.-P., Kügler, S., Ma, Z.-K., Shen, Y., & Schachner, M. (2011) · Neuroreport · doi:10.1097/wnr.0b013e328348bff5 · Cited by 8 · cited 1×
“AAV2 diffuses less readily through both the brain and spinal cord parenchyma when compared against other serotypes, and therefore mediates transduction over a smaller area [19, 28, 32, 33].”
BackgroundAn acidic oligopeptide displayed on AAV2 improves axial muscle tropism after systemic delivery
Lee, N., Falk, D. J., Byrne, B. J., Conlon, T. J., Clement, N., Porvasnik, S., Jorgensen, M., Potter, M., Erger, K. E., Watson, R., et al. (2012) · Genetic Vaccines and Therapy · doi:10.1186/1479-0556-10-3 · Cited by 6 · cited 1×
“To date, improved targeting of skeletal muscle [81, 82], cardiac muscle [83], vasculature [84– 86], lung [87, 88], diseased brain endothelial cells [89], retina [90], ovarian cancer cells [91] and breast cancer cells [88] has been reported.”
Background
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Naso, M. F., Tomkowicz, B., Perry, W. L., & Strohl, W. R. (2017) · BioDrugs · doi:10.1007/s40259-017-0234-5 · Cited by 1,362
“For example, the CMV promoter has been shown to be silenced in the central nervous system (CNS) [16].”
BackgroundInfluentialTherapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality
Hudry, E., & Vandenberghe, L. H. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.017 · Cited by 384
Self-citationAdeno-Associated Virus-Based Gene Therapy for CNS Diseases
Hocquemiller, M., Giersch, L., Audrain, M., Parker, S., & Cartier, N. (2016) · Human Gene Therapy · doi:10.1089/hum.2016.087 · Cited by 291
Viral vectors for therapy of neurologic diseases
Choudhury, S. R., Hudry, E., Maguire, C. A., Sena-Esteves, M., Breakefield, X. O., & Grandi, P. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.02.013 · Cited by 190
“Recent efforts at capsid reengineering (Castle et al., 2016) have led to the generation of two AAV capsid variants, AAV-AS (Choudhury et al.”
BackgroundA Student’s Guide to Neural Circuit Tracing
Saleeba, C., Dempsey, B., Le, S., Goodchild, A., & McMullan, S. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00897 · Cited by 153
Metadata
- Authors
- Castle, M. J., Turunen, H. T., Vandenberghe, L. H., & Wolfe, J. H.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Massachusetts Eye and Ear Infirmary (US)
- Corresponding author
- Wolfe, John H.
- Venue
- Methods in Molecular Biology
- Publisher
- Springer New York
- Published
- 2016
- Volume
- 1382
- Pages
- 133-149
- ISSN
- 1064-3745 (ISSN-L)
- 1940-6029
- PMC
- PMC4993104
- OpenAlex
- W2176154815
- Cited by
- 151
- References
- 135
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 22 · 2023: 15 · 2022: 10 · 2021: 24 · 2020: 14 · 2019: 17 · 2018: 8 · 2017: 11 · 2016: 5
- FWCI
- 23.28
- Type
- book chapter
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Methods in molecular biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1dp1od008267-01)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK063973)
- National Institute of Neurological Disorders and Stroke (R01NS038690, T32NS007413)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01HD079066)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- adeno-associated virus, AAV capsid engineering, viral tropism, retinal gene delivery, receptor binding, peptide insertion, directed evolution, neutralizing antibodies, transduction efficiency, vector selection
- MeSH terms
- Dependovirus, Animals, Capsid, Central Nervous System, Genetic Vectors, Humans, Organ Specificity, Retina, Gene Transfer Techniques, Viral Tropism
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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