Atchison, R. W., Casto, B. C. & Hammon, W. M. Adenovirus-associated defective virus particles. Science 149, 754–756 (1965). This report is among the first to identify by electron microscopy the presence of AAV as a defective virus in simian AdV preparations.
Hoggan, M. D., Blacklow, N. R. & Rowe, W. P. Studies of small DNA viruses found in various adenovirus preparations: physical, biological, and immunological characteristics. Proc. Natl Acad. Sci. USA 55, 1467–1474 (1966).
Blacklow, N. R., Hoggan, M. D. & Rowe, W. P. Isolation of adenovirus-associated viruses from man. Proc. Natl Acad. Sci. USA 58, 1410–1415 (1967).
Carter, B. J. Adeno-associated virus and the development of adeno-associated virus vectors: a historical perspective. Mol. Ther. 10, 981–989 (2004).
Berns, K. I. My life with adeno-associated virus: a long time spent studying a short genome. DNA Cell Biol. 32, 342–347 (2013).
Hastie, E. & Samulski, R. J. Adeno-associated virus at 50: a golden anniversary of discovery, research, and gene therapy success—a personal perspective. Hum. Gene Ther. 26, 257–265 (2015).
Crawford, L. V., Follett, E. A., Burdon, M. G. & McGeoch, D. J. The DNA of a minute virus of mice. J. Gen. Virol. 4, 37–46 (1969).
Rose, J. A., Berns, K. I., Hoggan, M. D. & Koczot, F. J. Evidence for a single-stranded adenovirus-associated virus genome: formation of a DNA density hybrid on release of viral DNA. Proc. Natl Acad. Sci. USA 64, 863–869 (1969).
Carter, B. J., Khoury, G. & Denhardt, D. T. Physical map and strand polarity of specific fragments of adenovirus-associated virus DNA produced by endonuclease R-EcoRI. J. Virol. 16, 559–568 (1975).
Lusby, E., Fife, K. H. & Berns, K. I. Nucleotide sequence of the inverted terminal repetition in adeno-associated virus DNA. J. Virol. 34, 402–409 (1980).
Carter, B. J., Khoury, G. & Rose, J. A. Adenovirus-associated virus multiplication. IX. Extent of transcription of the viral genome in vivo. J. Virol. 10, 1118–1125 (1972).
Hauswirth, W. W. & Berns, K. I. Origin and termination of adeno-associated virus DNA replication. Virology 78, 488–499 (1977).
Marcus, C. J., Laughlin, C. A. & Carter, B. J. Adeno-associated virus RNA transcription in vivo. Eur. J. Biochem. 121, 147–154 (1981).
Berns, K. I., Pinkerton, T. C., Thomas, G. F. & Hoggan, M. D. Detection of adeno-associated virus (AAV)-specific nucleotide sequences in DNA isolated from latently infected Detroit 6 cells. Virology 68, 556–560 (1975).
Cheung, A. K., Hoggan, M. D., Hauswirth, W. W. & Berns, K. I. Integration of the adeno-associated virus genome into cellular DNA in latently infected human Detroit 6 cells. J. Virol. 33, 739–748 (1980).
Kotin, R. M. & Berns, K. I. Organization of adeno-associated virus DNA in latently infected Detroit 6 cells. Virology 170, 460–467 (1989).
Kotin, R. M. et al. Site-specific integration by adeno-associated virus. Proc. Natl Acad. Sci. USA 87, 2211–2215 (1990).
Kotin, R. M., Menninger, J. C., Ward, D. C. & Berns, K. I. Mapping and direct visualization of a region-specific viral DNA integration site on chromosome 19q13-qter. Genomics 10, 831–834 (1991). References 17 and 18 are the first reports to describe latent AAV genomes integrating into a specific region of human chromosome 19, which was later characterized and named AAVS1.
Linden, R. M., Ward, P., Giraud, C., Winocour, E. & Berns, K. I. Site-specific integration by adeno-associated virus. Proc. Natl Acad. Sci. USA 93, 11288–11294 (1996).
Myers, M. W. & Carter, B. J. Assembly of adeno-associated virus. Virology 102, 71–82 (1980).
Samulski, R. J., Berns, K. I., Tan, M. & Muzyczka, N. Cloning of adeno-associated virus into pBR322: rescue of intact virus from the recombinant plasmid in human cells. Proc. Natl Acad. Sci. USA 79, 2077–2081 (1982).
Laughlin, C. A., Tratschin, J. D., Coon, H. & Carter, B. J. Cloning of infectious adeno-associated virus genomes in bacterial plasmids. Gene 23, 65–73 (1983).
Srivastava, A., Lusby, E. W. & Berns, K. I. Nucleotide sequence and organization of the adeno-associated virus 2 genome. J. Virol. 45, 555–564 (1983).
Yla-Herttuala, S. Endgame: glybera finally recommended for approval as the first gene therapy drug in the European union. Mol. Ther. 20, 1831–1832 (2012).
Colella, P., Ronzitti, G. & Mingozzi, F. Emerging issues in AAV-mediated in vivo gene therapy. Mol. Ther. Methods Clin. Dev. 8, 87–104 (2018).
Wang, D. & Gao, G. State-of-the-art human gene therapy: part I. Gene delivery technologies. Discov. Med. 18, 67–77 (2014).
Vannucci, L., Lai, M., Chiuppesi, F., Ceccherini-Nelli, L. & Pistello, M. Viral vectors: a look back and ahead on gene transfer technology. New Microbiol. 36, 1–22 (2013).
Yin, H. et al. Non-viral vectors for gene-based therapy. Nat. Rev. Genet. 15, 541–555 (2014).
Muzyczka, N. & Berns, K. in Fields Virology Vol. 2 (eds Knipe, D. et al.) 2327–2359 (Lippincott, Williams and Wilkins, 2001).
Sonntag, F., Schmidt, K. & Kleinschmidt, J. A. A viral assembly factor promotes AAV2 capsid formation in the nucleolus. Proc. Natl Acad. Sci. USA 107, 10220–10225 (2010).
Sonntag, F. et al. The assembly-activating protein promotes capsid assembly of different adeno-associated virus serotypes. J. Virol. 85, 12686–12697 (2011).
Samulski, R. J. et al. Targeted integration of adeno-associated virus (AAV) into human chromosome 19. EMBO J. 10, 3941–3950 (1991).
Philpott, N. J., Gomos, J., Berns, K. I. & Falck-Pedersen, E. A p5 integration efficiency element mediates Rep-dependent integration into AAVS1 at chromosome 19. Proc. Natl Acad. Sci. USA 99, 12381–12385 (2002).
Linden, R. M., Winocour, E. & Berns, K. I. The recombination signals for adeno-associated virus site-specific integration. Proc. Natl Acad. Sci. USA 93, 7966–7972 (1996).
Dong, J. Y., Fan, P. D. & Frizzell, R. A. Quantitative analysis of the packaging capacity of recombinant adeno-associated virus. Hum. Gene Ther. 7, 2101–2112 (1996).
Denard, J. et al. AAV-8 and AAV-9 vectors cooperate with serum proteins differently than AAV-1 and AAV-6. Mol. Ther. Methods Clin. Dev. 10, 291–302 (2018).
Huang, L. Y., Halder, S. & Agbandje-McKenna, M. Parvovirus glycan interactions. Curr. Opin. Virol. 7, 108–118 (2014).
Agbandje-McKenna, M. & Kleinschmidt, J. AAV capsid structure and cell interactions. Methods Mol. Biol. 807, 47–92 (2011). This book chapter serves as an excellent general review on AAV capsid biology, function and structure and provides detailed descriptions for AAV purification and characterization studies.
Nonnenmacher, M. & Weber, T. Intracellular transport of recombinant adeno-associated virus vectors. Gene Ther. 19, 649–658 (2012).
Pillay, S. et al. An essential receptor for adeno-associated virus infection. Nature 530, 108–112 (2016).
Pillay, S. et al. Adeno-associated virus (AAV) serotypes have distinctive interactions with domains of the cellular AAV receptor. J. Virol. 91, e00391-17 (2017).
Summerford, C., Johnson, J. S. & Samulski, R. J. AAVR: a multi-serotype receptor for AAV. Mol. Ther. 24, 663–666 (2016).
Drouin, L. M. & Agbandje-McKenna, M. Adeno-associated virus structural biology as a tool in vector development. Future Virol. 8, 1183–1199 (2013).
Duan, D. et al. Dynamin is required for recombinant adeno-associated virus type 2 infection. J. Virol. 73, 10371–10376 (1999).
Bartlett, J. S., Wilcher, R. & Samulski, R. J. Infectious entry pathway of adeno-associated virus and adeno-associated virus vectors. J. Virol. 74, 2777–2785 (2000).
Nonnenmacher, M. & Weber, T. Adeno-associated virus 2 infection requires endocytosis through the CLIC/GEEC pathway. Cell Host Microbe 10, 563–576 (2011).
Sonntag, F., Bleker, S., Leuchs, B., Fischer, R. & Kleinschmidt, J. A. Adeno-associated virus type 2 capsids with externalized VP1/VP2 trafficking domains are generated prior to passage through the cytoplasm and are maintained until uncoating occurs in the nucleus. J. Virol. 80, 11040–11054 (2006).
Xiao, P. J. & Samulski, R. J. Cytoplasmic trafficking, endosomal escape, and perinuclear accumulation of adeno-associated virus type 2 particles are facilitated by microtubule network. J. Virol. 86, 10462–10473 (2012).
Xiao, W. et al. Adenovirus-facilitated nuclear translocation of adeno-associated virus type 2. J. Virol. 76, 11505–11517 (2002).
Nicolson, S. C. & Samulski, R. J. Recombinant adeno-associated virus utilizes host cell nuclear import machinery to enter the nucleus. J. Virol. 88, 4132–4144 (2014).
Kelich, J. M. et al. Super-resolution imaging of nuclear import of adeno-associated virus in live cells. Mol. Ther. Methods Clin. Dev. 2, 15047 (2015).
Fisher, K. J. et al. Transduction with recombinant adeno-associated virus for gene therapy is limited by leading-strand synthesis. J. Virol. 70, 520–532 (1996).
Ferrari, F. K., Samulski, T., Shenk, T. & Samulski, R. J. Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J. Virol. 70, 3227–3234 (1996).
Zhou, X. et al. Adeno-associated virus of a single-polarity DNA genome is capable of transduction in vivo. Mol. Ther. 16, 494–499 (2008).
Zhong, L. et al. Single-polarity recombinant adeno-associated virus 2 vector-mediated transgene expression in vitro and in vivo: mechanism of transduction. Mol. Ther. 16, 290–295 (2008).
Nakai, H., Storm, T. A. & Kay, M. A. Recruitment of single-stranded recombinant adeno-associated virus vector genomes and intermolecular recombination are responsible for stable transduction of liver in vivo. J. Virol. 74, 9451–9463 (2000).
McCarty, D. M. et al. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther. 10, 2112–2118 (2003).
Wang, Z. et al. Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo. Gene Ther. 10, 2105–2111 (2003).
Duan, D. et al. Circular intermediates of recombinant adeno-associated virus have defined structural characteristics responsible for long-term episomal persistence in muscle tissue. J. Virol. 72, 8568–8577 (1998). This study formally demonstrates that rAAVs show stability and long-term persistence in tissues as circularized monomers and concatemers through recombination to form episomal genomes.
Duan, D., Yan, Z., Yue, Y. & Engelhardt, J. F. Structural analysis of adeno-associated virus transduction circular intermediates. Virology 261, 8–14 (1999).
Drouin, L. M. et al. Cryo-electron microscopy reconstruction and stability studies of the wild type and the R432A variant of adeno-associated virus type 2 reveal that capsid structural stability is a major factor in genome packaging. J. Virol. 90, 8542–8551 (2016).
Gurda, B. L. et al. Capsid antibodies to different adeno-associated virus serotypes bind common regions. J. Virol. 87, 9111–9124 (2013).
Gao, G. et al. Clades of Adeno-associated viruses are widely disseminated in human tissues. J. Virol. 78, 6381–6388 (2004). This study explores the diversity of AAV proviral sequences derived from human and NHP tissues and establishes the classification for the six AAV clades (A–F).
Gao, G. P. et al. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc. Natl Acad. Sci. USA 99, 11854–11859 (2002). This study identifies AAV7 and AAV8 in rhesus macaques by molecular cloning methods and establishes AAVs derived from NHPs as promising capsids for vectorization and therapeutic application.
Gao, G. et al. Adeno-associated viruses undergo substantial evolution in primates during natural infections. Proc. Natl Acad. Sci. USA 100, 6081–6086 (2003).
Schnepp, B. C., Jensen, R. L., Chen, C. L., Johnson, P. R. & Clark, K. R. Characterization of adeno-associated virus genomes isolated from human tissues. J. Virol. 79, 14793–14803 (2005).
Schnepp, B. C., Jensen, R. L., Clark, K. R. & Johnson, P. R. Infectious molecular clones of adeno-associated virus isolated directly from human tissues. J. Virol. 83, 1456–1464 (2009).
Smith, L. J. et al. Gene transfer properties and structural modeling of human stem cell-derived AAV. Mol. Ther. 22, 1625–1634 (2014).
Smith, L. J. et al. Stem cell-derived clade F AAVs mediate high-efficiency homologous recombination-based genome editing. Proc. Natl Acad. Sci. USA 115, E7379–E7388 (2018). This report describes the isolation of haematopoietic stem cell-derived AAVs that have the capacity to mediate gene editing via homologous recombination of the vector genome as a template without the need for exogenous nucleases.
Calcedo, R. et al. Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin. Vaccine Immunol. 18, 1586–1588 (2011).
Huser, D. et al. High prevalence of infectious adeno-associated virus (AAV) in human peripheral blood mononuclear cells indicative of T lymphocytes as sites of AAV persistence. J. Virol. 91, e02137–16 (2017).
Chen, C. L. et al. Molecular characterization of adeno-associated viruses infecting children. J. Virol. 79, 14781–14792 (2005).
Calcedo, R., Vandenberghe, L. H., Gao, G., Lin, J. & Wilson, J. M. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis. 199, 381–390 (2009).
Halbert, C. L. et al. Prevalence of neutralizing antibodies against adeno-associated virus (AAV) types 2, 5, and 6 in cystic fibrosis and normal populations: Implications for gene therapy using AAV vectors. Hum. Gene Ther. 17, 440–447 (2006).
Boutin, S. 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. 21, 704–712 (2010).
Yates, V. J., el-Mishad, A. M., McCormick, K. J. & Trentin, J. J. Isolation and characterization of an Avian adenovirus-associated virus. Infect. Immun. 7, 973–980 (1973).
Lochrie, M. A. et al. Adeno-associated virus (AAV) capsid genes isolated from rat and mouse liver genomic DNA define two new AAV species distantly related to AAV-5. Virology 353, 68–82 (2006).
Arbetman, A. E. et al. Novel caprine adeno-associated virus (AAV) capsid (AAV-Go.1) is closely related to the primate AAV-5 and has unique tropism and neutralization properties. J. Virol. 79, 15238–15245 (2005).
Clarke, J. K., McFerran, J. B., McKillop, E. R. & Curran, W. L. Isolation of an adeno associated virus from sheep. Arch. Virol. 60, 171–176 (1979).
Bello, A. et al. Isolation and evaluation of novel adeno-associated virus sequences from porcine tissues. Gene Ther. 16, 1320–1328 (2009).
Li, Y. et al. Host range, prevalence, and genetic diversity of adenoviruses in bats. J. Virol. 84, 3889–3897 (2010).
Farkas, S. L. et al. A parvovirus isolated from royal python (Python regius) is a member of the genus Dependovirus. J. Gen. Virol. 85, 555–561 (2004).
Myrup, A. C., Mohanty, S. B. & Hetrick, F. M. Isolation and characterization of adeno-associated viruses from bovine adenovirus types 1 and 2. Am. J. Vet. Res. 37, 907–910 (1976).
Bello, A. et al. Novel adeno-associated viruses derived from pig tissues transduce most major organs in mice. Sci. Rep. 4, 6644 (2014).
Eid, J. et al. Real-time DNA sequencing from single polymerase molecules. Science 323, 133–138 (2009).
Xu, G. et al. High-throughput sequencing of AAV proviral libraries from the human population reveals novel variants with unprecedented intra- and inter-tissue diversity. Mol. Ther. 24, S4 (2016).
Chen, Y. H., Chang, M. & Davidson, B. L. Molecular signatures of disease brain endothelia provide new sites for CNS-directed enzyme therapy. Nat. Med. 15, 1215–1218 (2009).
Girod, A. et al. Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2. Nat. Med. 5, 1052–1056 (1999).
Warrington, K. H. Jr et al. Adeno-associated virus type 2 VP2 capsid protein is nonessential and can tolerate large peptide insertions at its N terminus. J. Virol. 78, 6595–6609 (2004).
Yang, Q. et al. Development of novel cell surface CD34-targeted recombinant adenoassociated virus vectors for gene therapy. Hum. Gene Ther. 9, 1929–1937 (1998).
Munch, R. C. et al. Off-target-free gene delivery by affinity-purified receptor-targeted viral vectors. Nat. Commun. 6, 6246 (2015).
Asokan, A. et al. Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat. Biotechnol. 28, 79–82 (2010).
Bowles, D. E. et al. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol. Ther. 20, 443–455 (2012).
Zhang, C. et al. Development of next generation adeno-associated viral vectors capable of selective tropism and efficient gene delivery. Biomaterials 80, 134–145 (2016).
Kelemen, R. E. et al. A precise chemical strategy to alter the receptor specificity of the adeno-associated virus. Angew. Chem. Int. Ed. 55, 10645–10649 (2016).
Yao, T. et al. Site-specific pegylated adeno-associated viruses with increased serum stability and reduced immunogenicity. Molecules 22, E1155 (2017).
Katrekar, D., Moreno, A. M., Chen, G., Worlikar, A. & Mali, P. Oligonucleotide conjugated multi-functional adeno-associated viruses. Sci. Rep. 8, 3589 (2018).
Zhong, L. et al. Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses. Proc. Natl Acad. Sci. USA 105, 7827–7832 (2008).
Tordo, J. et al. A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency. Brain 141, 2014–2031 (2018).
Wang, D. et al. A rationally engineered capsid variant of AAV9 for systemic CNS-directed and peripheral tissue-detargeted gene delivery in neonates. Mol. Ther. Methods Clin. Dev. 9, 234–246 (2018).
Tse, L. V. et al. Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion. Proc. Natl Acad. Sci. USA 114, E4812–E4821 (2017).
Paulk, N. K. et al. Bioengineered AAV capsids with combined high human liver transduction in vivo and unique humoral seroreactivity. Mol. Ther. 26, 289–303 (2018).
Maheshri, N., Koerber, J. T., Kaspar, B. K. & Schaffer, D. V. Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat. Biotechnol. 24, 198–204 (2006). This study demonstrates the feasibility of directed evolution of AAV vectors for desired clinical features.
Koerber, J. T., Jang, J. H. & Schaffer, D. V. DNA shuffling of adeno-associated virus yields functionally diverse viral progeny. Mol. Ther. 16, 1703–1709 (2008).
Kotterman, M. A. & Schaffer, D. V. Engineering adeno-associated viruses for clinical gene therapy. Nat. Rev. Genet. 15, 445–451 (2014).
Choudhury, S. R. et al. In vivo selection yields AAV-B1 capsid for central nervous system and muscle gene therapy. Mol. Ther. 24, 1247–1257 (2016).
Li, W. et al. Generation of novel AAV variants by directed evolution for improved CFTR delivery to human ciliated airway epithelium. Mol. Ther. 17, 2067–2077 (2009).
Yang, L. et al. A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection. Proc. Natl Acad. Sci. USA 106, 3946–3951 (2009).
Sallach, J. et al. Tropism-modified AAV vectors overcome barriers to successful cutaneous therapy. Mol. Ther. 22, 929–939 (2014).
Deverman, B. E. et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat. Biotechnol. 34, 204–209 (2016). This paper describes the development of a Cre recombination-based method to screen AAV capsid libraries in mice and through this approach identifies AAV-PHP.B.
Lisowski, L. et al. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 506, 382–386 (2014). This study utilizes a human xenograft mouse model to identify an AAV capsid that has tropism to human hepatocytes, aiming to overcome the limitation of using non-human evolution systems.
Grimm, D. et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J. Virol. 82, 5887–5911 (2008).
Gray, S. J. et al. Directed evolution of a novel adeno-associated virus (AAV) vector that crosses the seizure-compromised blood-brain barrier (BBB). Mol. Ther. 18, 570–578 (2010).
Wooley, D. P. et al. A directed evolution approach to select for novel Adeno-associated virus capsids on an HIV-1 producer T cell line. J. Virol. Methods 250, 47–54 (2017).
Chan, K. Y. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172–1179 (2017).
Matsuzaki, Y. et al. Intravenous administration of the adeno-associated virus-PHP. B capsid fails to upregulate transduction efficiency in the marmoset brain. Neurosci. Lett. 665, 182–188 (2017).
Hordeaux, J. et al. The neurotropic properties of AAV-PHP. B are limited to C57BL/6J mice. Mol. Ther. 26, 664–668 (2018).
Hinderer, C. et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN. Hum. Gene Ther. 29, 285–298 (2018).
Marsic, D. et al. Vector design Tour de Force: integrating combinatorial and rational approaches to derive novel adeno-associated virus variants. Mol. Ther. 22, 1900–1909 (2014).
Zinn, E. et al. In silico reconstruction of the viral evolutionary lineage yields a potent gene therapy vector. Cell Rep. 12, 1056–1068 (2015). This manuscript demonstrates the power of in silico AAV capsid design and the development of non-natural capsids termed ancestral AAVs with potent transduction characteristics.
Landegger, L. D. et al. A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat. Biotechnol. 35, 280–284 (2017).
Smith, R. H. et al. Germline viral “fossils” guide in silico reconstruction of a mid-Cenozoic era marsupial adeno-associated virus. Sci. Rep. 6, 28965 (2016).
Lu, J., Zhang, F. & Kay, M. A. A mini-intronic plasmid (MIP): a novel robust transgene expression vector in vivo and in vitro. Mol. Ther. 21, 954–963 (2013).
Lu, J. et al. A 5’ noncoding exon containing engineered intron enhances transgene expression from recombinant AAV vectors in vivo. Hum. Gene Ther. 28, 125–134 (2017).
Donello, J. E., Loeb, J. E. & Hope, T. J. Woodchuck hepatitis virus contains a tripartite posttranscriptional regulatory element. J. Virol. 72, 5085–5092 (1998).
Loeb, J. E., Cordier, W. S., Harris, M. E., Weitzman, M. D. & Hope, T. J. Enhanced expression of transgenes from adeno-associated virus vectors with the woodchuck hepatitis virus posttranscriptional regulatory element: implications for gene therapy. Hum. Gene Ther. 10, 2295–2305 (1999).
Kingsman, S. M., Mitrophanous, K. & Olsen, J. C. Potential oncogene activity of the woodchuck hepatitis post-transcriptional regulatory element (WPRE). Gene Ther. 12, 3–4 (2005).
Patel, M. & Olsen, J. C. Optimizing the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) for safety and function in lentiviral vectors. Mol. Ther. 11, S322 (2005).
Wang, L., Wang, H., Bell, P., McMenamin, D. & Wilson, J. M. Hepatic gene transfer in neonatal mice by adeno-associated virus serotype 8 vector. Hum. Gene Ther. 23, 533–539 (2012).
Gessler, D. J. et al. Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease. JCI Insight 2, e90807 (2017).
Nathwani, A. C. et al. Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood 107, 2653–2661 (2006).
Ronzitti, G. et al. A translationally optimized AAV-UGT1A1 vector drives safe and long-lasting correction of Crigler-Najjar syndrome. Mol. Ther. Methods Clin. Dev. 3, 16049 (2016).
Grimm, D., Pandey, K. & Kay, M. A. Adeno-associated virus vectors for short hairpin RNA expression. Methods Enzymol. 392, 381–405 (2005).
Garg, S. K. et al. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome. J. Neurosci. 33, 13612–13620 (2013).
Gadalla, K. K. E. et al. Development of a novel AAV gene therapy cassette with improved safety features and efficacy in a mouse model of Rett syndrome. Mol. Ther. Methods Clin. Dev. 5, 180–190 (2017).
Golebiowski, D. et al. Direct intracranial injection of AAVrh8 encoding monkey beta-N-acetylhexosaminidase causes neurotoxicity in the primate brain. Hum. Gene Ther. 28, 510–522 (2017).
Grimm, D. et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441, 537–541 (2006).
McBride, J. L. et al. Artificial mi-RNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc. Natl Acad. Sci. USA 105, 5868–5873 (2008).
Boudreau, R. L., Martins, I. & Davidson, B. L. Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo. Mol. Ther. 17, 169–175 (2009).
Stoica, L. et al. AAV delivered artificial microRNA extends survival and delays paralysis in an Amyotrophic Lateral Sclerosis mouse model. Ann. Neurol. 79, 687–700 (2016).
Pfister, E. L. et al. Artificial mi-RNAs reduce human mutant huntingtin throughout the striatum in a transgenic sheep model of Huntington’s disease. Hum. Gene Ther. 29, 663–673 (2018).
Pfister, E. L. et al. Safe and efficient silencing with a Pol II, but not a Pol lII, promoter expressing an artificial miRNA targeting human huntingtin. Mol. Ther. Nucleic Acids. 7, 324–334 (2017).
Gray, S. J. et al. Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors. Hum. Gene Ther. 22, 1143–1153 (2011).
Brown, B. D., Venneri, M. A., Zingale, A., Sergi Sergi, L. & Naldini, L. Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nat. Med. 12, 585–591 (2006).
Xie, J. et al. MicroRNA-regulated, systemically delivered rAAV9: a step closer to CNS-restricted transgene expression. Mol. Ther. 19, 526–535 (2011).
Qiao, C. et al. Liver-specific microRNA-122 target sequences incorporated in AAV vectors efficiently inhibits transgene expression in the liver. Gene Ther. 18, 403–410 (2011).
Geisler, A. et al. microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors. Gene Ther. 18, 199–209 (2011).
Majowicz, A. et al. Mir-142-3p target sequences reduce transgene-directed immunogenicity following intramuscular adeno-associated virus 1 vector-mediated gene delivery. J. Gene Med. 15, 219–232 (2013).
Boisgerault, F. et al. Prolonged gene expression in muscle is achieved without active immune tolerance using microrRNA 142.3p-regulated rAAV gene transfer. Hum. Gene Ther. 24, 393–405 (2013).
Duan, D. Systemic AAV micro-dystrophin gene therapy for Duchenne muscular dystrophy. Mol. Ther. 26, 2337–2356 (2018). This review comprehensively describes the history, current status and future goals for AAV micro-dystrophin gene therapy.
England, S. B. et al. Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature 343, 180–182 (1990).
Sondergaard, P. C. et al. AAV. Dysferlin overlap vectors restore function in dysferlinopathy animal models. Ann. Clin. Transl Neurol. 2, 256–270 (2015).
Zhang, W., Li, L., Su, Q., Gao, G. & Khanna, H. Gene therapy using a miniCEP290 fragment delays photoreceptor degeneration in a mouse model of leber congenital amaurosis. Hum. Gene Ther. 29, 42–50 (2018).
Duan, D., Yue, Y., Yan, Z. & Engelhardt, J. F. A new dual-vector approach to enhance recombinant adeno-associated virus-mediated gene expression through intermolecular cis activation. Nat. Med. 6, 595–598 (2000).
Sun, L., Li, J. & Xiao, X. Overcoming adeno-associated virus vector size limitation through viral DNA heterodimerization. Nat. Med. 6, 599–602 (2000).
Nakai, H., Storm, T. A. & Kay, M. A. Increasing the size of rAAV-mediated expression cassettes in vivo by intermolecular joining of two complementary vectors. Nat. Biotechnol. 18, 527–532 (2000).
McClements, M. E. & MacLaren, R. E. Adeno-associated virus (AAV) dual vector strategies for gene therapy encoding large transgenes. Yale J. Biol. Med. 90, 611–623 (2017).
Lai, Y., Yue, Y., Bostick, B. & Duan, D. in Muscle Gene Therapy (ed. Duan, D.) 205–218 (Springer, 2010).
Duan, D., Yue, Y. & Engelhardt, J. F. Expanding AAV packaging capacity with trans-splicing or overlapping vectors: a quantitative comparison. Mol. Ther. 4, 383–391 (2001).
Lai, Y. et al. Efficient in vivo gene expression by trans-splicing adeno-associated viral vectors. Nat. Biotechnol. 23, 1435–1439 (2005).
Ghosh, A., Yue, Y., Lai, Y. & Duan, D. A hybrid vector system expands adeno-associated viral vector packaging capacity in a transgene-independent manner. Mol. Ther. 16, 124–130 (2008).
Aranko, A. S., Wlodawer, A. & Iwai, H. Nature’s recipe for splitting inteins. Protein Eng. Des. Sel. 27, 263–271 (2014).
Li, J., Sun, W., Wang, B., Xiao, X. & Liu, X. Q. Protein trans-splicing as a means for viral vector-mediated in vivo gene therapy. Hum. Gene Ther. 19, 958–964 (2008).
Truong, D. J. et al. Development of an intein-mediated split-Cas9 system for gene therapy. Nucleic Acids Res. 43, 6450–6458 (2015).
Chew, W. L. et al. A multifunctional AAV-CRISPR-Cas9 and its host response. Nat. Methods 13, 868–874 (2016).
Yang, Y. et al. A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat. Biotechnol. 34, 334–338 (2016).
Suzuki, K. et al. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature 540, 144–149 (2016).
Brown, A., Li, J., Zhu, Y., Su, Q. & Gao, G. rAAV-mediated nuclease-assisted vector integration (rAAV-NAVI) promotes highly efficient and stable transgene expression in somatic tissues. Mol. Ther. 26, S434 (2018).
Barzel, A. et al. Promoterless gene targeting without nucleases ameliorates haemophilia B in mice. Nature 517, 360–364 (2015).
Borel, F. et al. Survival advantage of both human hepatocyte xenografts and genome-edited hepatocytes for treatment of alpha-1 antitrypsin deficiency. Mol. Ther. 25, 2477–2489 (2017).
Russell, D. W. & Hirata, R. K. Human gene targeting by viral vectors. Nat. Genet. 18, 325–330 (1998).
Hagedorn, C. et al. S/MAR element facilitates episomal long-term persistence of adeno-associated virus vector genomes in proliferating cells. Hum. Gene Ther. 28, 1169–1179 (2017).
Piechaczek, C., Fetzer, C., Baiker, A., Bode, J. & Lipps, H. J. A vector based on the SV40 origin of replication and chromosomal S/MARs replicates episomally in CHO cells. Nucleic Acids Res. 27, 426–428 (1999).
Kattenhorn, L. M. et al. Adeno-associated virus gene therapy for liver disease. Hum. Gene Ther. 27, 947–961 (2016).
Wang, D., Zhong, L., Nahid, M. A. & Gao, G. The potential of adeno-associated viral vectors for gene delivery to muscle tissue. Expert Opin. Drug Deliv. 11, 345–364 (2014).
Bass-Stringer, S. et al. Adeno-associated virus gene therapy: translational progress and future prospects in the treatment of heart failure. Heart Lung Circ. 27, 1285–1300 (2018).
Hocquemiller, M., Giersch, L., Audrain, M., Parker, S. & Cartier, N. Adeno-associated virus-based gene therapy for CNS diseases. Hum. Gene Ther. 27, 478–496 (2016).
Deverman, B. E., Ravina, B. M., Bankiewicz, K. S., Paul, S. M. & Sah, D. W. Y. Gene therapy for neurological disorders: progress and prospects. Nat. Rev. Drug Discov. 17, 641–659 (2018). This is an up-to-date review on the current trends and challenges for AAV-based CNS gene therapy.
Petit, L., Khanna, H. & Punzo, C. Advances in gene therapy for diseases of the eye. Hum. Gene Ther. 27, 563–579 (2016).
Bennett, J. Taking stock of retinal gene therapy: looking back and moving forward. Mol. Ther. 25, 1076–1094 (2017). This is an excellent review written from the perspective of an eyewitness account that details the experimental challenges, critical benchmarks and scientists that played key roles in developing AAV-based retinal gene therapies.
Auricchio, A., Smith, A. J. & Ali, R. R. The future looks brighter after 25 years of retinal gene therapy. Hum. Gene Ther. 28, 982–987 (2017).
Russell, S. 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 390, 849–860 (2017). This key report summarizes the phase III clinical trial findings for the now FDA-approved and European Medicines Agency-approved drug voretigene neparvovec (AAV2-hRPE65v2), trade name Luxturna.
Foust, K. D. et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol. 27, 59–65 (2009).
Duque, S. et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol. Ther. 17, 1187–1196 (2009).
Zhang, H. et al. Several rAAV vectors efficiently cross the blood-brain barrier and transduce neurons and astrocytes in the neonatal mouse central nervous system. Mol. Ther. 19, 1440–1448 (2011).
Yang, B. et al. Intravasuclar delivery of rAAVRH.8 generates widespreading transduction of neuronal and glial cell types in the adult mouse central nervous system. Mol. Ther. 20, S203 (2012).
Foust, K. D. et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat. Biotechnol. 28, 271–274 (2010).
Foust, K. D. et al. Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Mol. Ther. 21, 2148–2159 (2013).
Borel, F. et al. Therapeutic rAAVrh10 mediated SOD1 silencing in adult SOD1(G93A) mice and nonhuman primates. Hum. Gene Ther. 27, 19–31 (2016).
Ahmed, S. S. et al. A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan mice. Mol. Ther. 21, 2136–2147 (2013).
Weismann, C. M. et al. Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan. Hum. Mol. Genet. 24, 4353–4364 (2015).
Fu, H., Dirosario, J., Killedar, S., Zaraspe, K. & McCarty, D. M. Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery. Mol. Ther. 19, 1025–1033 (2011).
Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722 (2017).
Burnett, J. R. & Hooper, A. J. Alipogene tiparvovec, an adeno-associated virus encoding the Ser(447)X variant of the human lipoprotein lipase gene for the treatment of patients with lipoprotein lipase deficiency. Curr. Opin. Mol. Ther. 11, 681–691 (2009).
Borel, F., Kay, M. A. & Mueller, C. Recombinant AAV as a platform for translating the therapeutic potential of RNA interference. Mol. Ther. 22, 692–701 (2014).
Xie, J. et al. Short DNA hairpins compromise recombinant adeno-associated virus genome homogeneity. Mol. Ther. 25, 1363–1374 (2017). This report reveals that vector designs harbouring strong secondary structure in the form of hairpins serve as scaffolds for genome truncation events during vector packaging.
Xie, J., Tai, P. W., Brown, A., Li, C. & Gao, G. A novel rAAV-amiRNA platform enables potent in vivo gene silencing and a ten-fold enhancement of on-target specificity over conventional shRNA vectors. Mol. Ther. 26, 436 (2018).
Abudayyeh, O. O. et al. RNA targeting with CRISPR-Cas13. Nature 550, 280–284 (2017).
Konermann, S. et al. Transcriptome engineering with RNA-targeting type VI-D CRISPR effectors. Cell 173, 665–676 (2018).
Thakore, P. I. et al. RNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors. Nat. Commun. 9, 1674 (2018).
Wang, D. et al. Adenovirus-mediated somatic genome editing of Pten by CRISPR/Cas9 in mouse liver in spite of Cas9-specific immune responses. Hum. Gene Ther. 26, 432–442 (2015).
Hynes, A. P. et al. Widespread anti-CRISPR proteins in virulent bacteriophages inhibit a range of Cas9 proteins. Nat. Commun. 9, 2919 (2018).
Jessup, M. et al. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation 124, 304–313 (2011).
Pepin, D. et al. AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer. Proc. Natl Acad. Sci. USA 112, E4418–E4427 (2015).
Johnson, P. R. et al. Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nat. Med. 15, 901–906 (2009).
Balazs, A. B. et al. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 481, 81–84 (2012).
Balazs, A. B. & West, A. P. Jr. Antibody gene transfer for HIV immunoprophylaxis. Nat. Immunol. 14, 1–5 (2013).
Gardner, M. R. et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature 519, 87–91 (2015).
Limberis, M. P. et al. Intranasal antibody gene transfer in mice and ferrets elicits broad protection against pandemic influenza. Sci. Transl Med. 5, 187ra172 (2013).
Fuchs, S. P. et al. AAV-delivered antibody mediates significant protective effects against SIVmac239 challenge in the absence of neutralizing activity. PLOS Pathog. 11, e1005090 (2015).
Ding, Q. et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ. Res. 115, 488–492 (2014).
Wang, L. et al. Meganuclease targeting of PCSK9 in macaque liver leads to stable reduction in serum cholesterol. Nat. Biotechnol. 36, 717–725 (2018).
Bakondi, B. et al. In Vivo CRISPR/Cas9 gene editing corrects retinal dystrophy in the S334ter-3 rat model of autosomal dominant retinitis pigmentosa. Mol. Ther. 24, 556–563 (2016).
Yin, H. et al. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat. Biotechnol. 32, 551–553 (2014).
Yin, H. et al. Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat. Biotechnol. 34, 328–333 (2016).
Song, C. Q. et al. In vivo genome editing partially restores alpha1-antitrypsin in a murine model of AAT deficiency. Hum. Gene Ther. 29, 853–860 (2018).
Shen, S. et al. Amelioration of alpha-1 antitrypsin deficiency diseases with genome editing in transgenic mice. Hum. Gene Ther. 29, 861–873 (2018).
Li, H. et al. In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature 475, 217–221 (2011).
Anguela, X. M. et al. Robust ZFN-mediated genome editing in adult hemophilic mice. Blood 122, 3283–3287 (2013).
Sharma, R. et al. In vivo genome editing of the albumin locus as a platform for protein replacement therapy. Blood 126, 1777–1784 (2015).
Long, C. et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 351, 400–403 (2016).
Nelson, C. E. et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351, 403–407 (2016).
Tabebordbar, M. et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351, 407–411 (2016).
Amoasii, L. et al. Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science 362, 86–91 (2018). This study is among the first to demonstrate the feasibility of AAV-based platforms to deliver CRISPR–Cas9 components in vivo to restore gene function, specifically dystrophin expression in a canine DMD model.
Wang, D. et al. Cas9-mediated allelic exchange repairs compound heterozygous recessive mutations in mice. Nat. Biotechnol. 36, 839–842 (2018).
Rees, H. A. & Liu, D. R. Base editing: precision chemistry on the genome and transcriptome of living cells. Nat. Rev. Genet. 19, 770–788 (2018).
Clement, N. & Grieger, J. C. Manufacturing of recombinant adeno-associated viral vectors for clinical trials. Mol. Ther. Methods Clin. Dev. 3, 16002 (2016).
Gao, G. & Sena-Esteves, M. in Molecular Cloning (eds Green, M. R. & Sambrook, J. R.) 1209–1330 (Cold Spring Harbor Laboratory Press, 2012).
Grieger, J. C., Soltys, S. M. & Samulski, R. J. Production of recombinant adeno-associated virus vectors using suspension HEK293 Cells and continuous harvest of vector from the culture media for GMP FIX and FLT1 clinical vector. Mol. Ther. 24, 287–297 (2016).
Thorne, B. A., Takeya, R. K. & Peluso, R. W. Manufacturing recombinant adeno-associated viral vectors from producer cell clones. Hum. Gene Ther. 20, 707–714 (2009).
Schnodt, M. & Buning, H. Improving the quality of adeno-associated viral vector preparations: the challenge of product-related impurities. Hum. Gene Ther. Methods 28, 101–108 (2017). This ‘Methods’ article comprehensively highlights the importance of identifying and limiting impurities in AAV vector preparations.
Burnham, B. et al. Analytical ultracentrifugation as an approach to characterize recombinant adeno-associated viral vectors. Hum. Gene Ther. Methods 26, 228–242 (2015).
Pierson, E. E., Keifer, D. Z., Asokan, A. & Jarrold, M. F. Resolving adeno-associated viral particle diversity with charge detection mass spectrometry. Anal. Chem. 88, 6718–6725 (2016).
De, B. P. et al. In vivo potency assay for adeno-associated virus-based gene therapy vectors using AAVrh.10 as an example. Hum. Gene Ther. Methods 29, 146–155 (2018).
Couto, L., Buchlis, G., Farjo, R. & High, K. A. Potency assay for AAV vector encoding retinal pigment epithelial 65 protein. Invest. Ophthalmol. Vis. Sci. 57, 12 (2016).
Drouin, L. M., Ciatto, C. & Horowitz, E. Evaluation of a biological potency assay for an AAV2. AADC vector used in the treatment of Parkinson’s disease. Mol. Ther. 26, 418 (2018).
Buck, T. M. et al. AAV serotype testing on cultured human donor retinal explants. Methods Mol. Biol. 1715, 275–288 (2018).
Orlans, H. O., Edwards, T. L., De Silva, S. R., Patricio, M. I. & MacLaren, R. E. Human retinal explant culture for ex vivo validation of AAV gene therapy. Methods Mol. Biol. 1715, 289–303 (2018).
Saveliev, A. et al. Accurate and rapid sequence analysis of adeno-associated virus plasmids by Illumina next-generation sequencing. Hum. Gene Ther. Methods 29, 201–211 (2018).
Lecomte, E. et al. Advanced characterization of DNA molecules in rAAV vector preparations by single-stranded virus next-generation sequencing. Mol. Ther. Nucleic Acids. 4, e260 (2015).
Tai, P. W. L. et al. Adeno-associated virus genome population sequencing achieves full vector genome resolution and reveals human-vector chimeras. Mol. Ther. Methods Clin. Dev. 9, 130–141 (2018).
Tai, P. W. L. et al. Heterogeneic genome encapsidation of rAAV-CRISPR/Cas9 vectors underscores potential limitations for promising in vivo gene-editing platforms. Mol. Ther. 26, S167 (2018).
Gigout, L. et al. Altering AAV tropism with mosaic viral capsids. Mol. Ther. 11, 856–865 (2005).
Pacouret, S. et al. AAV-ID: a rapid and robust assay for batch-to-batch consistency evaluation of AAV preparations. Mol. Ther. 25, 1375–1386 (2017).
Bennett, A. et al. Thermal stability as a determinant of AAV serotype identity. Mol. Ther. Methods Clin. Dev. 6, 171–182 (2017).
Rayaprolu, V. et al. Comparative analysis of adeno-associated virus capsid stability and dynamics. J. Virol. 87, 13150–13160 (2013).
Vandamme, C., Adjali, O. & Mingozzi, F. Unraveling the complex story of immune responses to AAV Vectors trial after trial. Hum. Gene Ther. 28, 1061–1074 (2017).
Mingozzi, F. & High, K. A. Overcoming the host immune response to adeno-associated virus gene delivery vectors: the race between clearance, tolerance, neutralization, and escape. Annu. Rev. Virol. 4, 511–534 (2017). This review details the current challenges for efficacious AAV-based gene therapies, focusing specifically on overcoming host immunological responses.
Manno, C. S. et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med. 12, 342–347 (2006). This investigation highlights the importance of immunological responses against the AAV capsid and consequent loss of transgene expression over time despite successful transduction of the target tissue.
Louis Jeune, V., Joergensen, J. A., Hajjar, R. J. & Weber, T. Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum. Gene Ther. Methods 24, 59–67 (2013).
Samaranch, L. et al. Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. Hum. Gene Ther. 23, 382–389 (2012).
Gray, S. J., Nagabhushan Kalburgi, S., McCown, T. J. & Jude Samulski, R. Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther. 20, 450–459 (2013).
Monteilhet, V. et al. A 10 patient case report on the impact of plasmapheresis upon neutralizing factors against adeno-associated virus (AAV) types 1, 2, 6, and 8. Mol. Ther. 19, 2084–2091 (2011).
Chicoine, L. G. et al. Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery. Mol. Ther. 22, 338–347 (2014).
Mingozzi, F. et al. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci. Transl Med. 5, 194ra192 (2013).
Nathwani, A. C. et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N. Engl. J. Med. 365, 2357–2365 (2011).
Nathwani, A. C. et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med. 371, 1994–2004 (2014).
Petry, H. et al. Effect of viral dose on neutralizing antibody response and transgene expression after AAV1 vector re-administration in mice. Gene Ther. 15, 54–60 (2008).
Corti, M. et al. Evaluation of readministration of a recombinant adeno-associated virus vector expressing acid alpha-glucosidase in Pompe disease: preclinical to clinical planning. Hum. Gene Ther. Clin. Dev. 26, 185–193 (2015).
Maldonado, R. A. et al. Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. Proc. Natl Acad. Sci. USA 112, E156–E165 (2015).
Kishimoto, T. K. et al. Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles. Nat. Nanotechnol. 11, 890–899 (2016).
Meliani, A. et al. Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration. Nat. Commun. 9, 4098 (2018).
Mingozzi, F. et al. CD8(+) T cell responses to adeno-associated virus capsid in humans. Nat. Med. 13, 419–422 (2007).
Flotte, T. R. & Buning, H. Severe toxicity in nonhuman primates and piglets with systemic high-dose administration of adeno-associated virus serotype 9-like vectors: putting patients first. Hum. Gene Ther. 29, 283–284 (2018).
Mueller, C. et al. Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression. J. Clin. Invest. 123, 5310–5318 (2013).
Biswas, M., Kumar, S. R. P., Terhorst, C. & Herzog, R. W. Gene therapy with regulatory T cells: a beneficial alliance. Front. Immunol. 9, 554 (2018).
Mendell, J. R. et al. Dystrophin immunity in Duchenne’s muscular dystrophy. N. Engl. J. Med. 363, 1429–1437 (2010).
Mingozzi, F. et al. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J. Clin. Invest. 111, 1347–1356 (2003).
Dobrzynski, E. et al. Induction of antigen-specific CD4+T cell anergy and deletion by in vivo viral gene transfer. Blood 104, 969–977 (2004).
Cao, O. et al. Induction and role of regulatory CD4+CD25+T cells in tolerance to the transgene product following hepatic in vivo gene transfer. Blood 110, 1132–1140 (2007).
Doerfler, P. A. et al. Copackaged AAV9 vectors promote simultaneous immune tolerance and phenotypic correction of Pompe disease. Hum. Gene Ther. 27, 43–59 (2016).
Hinderer, C. et al. Neonatal systemic AAV induces tolerance to CNS gene therapy in MPS I dogs and nonhuman primates. Mol. Ther. 23, 1298–1307 (2015).
Rogers, G. L. et al. Innate immune responses to AAV vectors. Front. Microbiol. 2, 194 (2011). This is an important review that highlights the significance of innate immunity against the AAV vector genome via TLR–MYD88 activation.
Martino, A. T. et al. The genome of self-complementary adeno-associated viral vectors increases Toll-like receptor 9-dependent innate immune responses in the liver. Blood 117, 6459–6468 (2011).
Faust, S. M. et al. CpG-depleted adeno-associated virus vectors evade immune detection. J. Clin. Invest. 123, 2994–3001 (2013).
Chan, Y. K. et al. Engineering AAV vectors to evade innate immune and inflammatory responses. Mol. Ther. 26, S457 (2018).
Clark, K. R., Voulgaropoulou, F., Fraley, D. M. & Johnson, P. R. Cell lines for the production of recombinant adeno-associated virus. Hum. Gene Ther. 6, 1329–1341 (1995).
Gao, G. P. et al. High-titer adeno-associated viral vectors from a Rep/Cap cell line and hybrid shuttle virus. Hum. Gene Ther. 9, 2353–2362 (1998).
Flotte, T. R. et al. Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing alpha1-antitrypsin: interim results. Hum. Gene Ther. 22, 1239–1247 (2011).
Thomas, D. L. et al. Scalable recombinant adeno-associated virus production using recombinant herpes simplex virus type 1 coinfection of suspension-adapted mammalian cells. Hum. Gene Ther. 20, 861–870 (2009).
Clement, N., Knop, D. R. & Byrne, B. J. Large-scale adeno-associated viral vector production using a herpesvirus-based system enables manufacturing for clinical studies. Hum. Gene Ther. 20, 796–806 (2009).
Kondratov, O. et al. Direct head-to-head evaluation of recombinant adeno-associated viral vectors manufactured in human versus insect cells. Mol. Ther. 25, 2661–2675 (2017).
Mietzsch, M. et al. OneBac 2.0: Sf9 cell lines for production of AAV1, AAV2, and AAV8 vectors with minimal encapsidation of foreign DNA. Hum. Gene Ther. Methods 28, 15–22 (2017).
Kotin, R. M. Large-scale recombinant adeno-associated virus production. Hum. Mol. Genet. 20, R2–R6 (2011).
Penaud-Budloo, M. et al. Accurate identification and quantification of DNA species by next-generation sequencing in adeno-associated viral vectors produced in insect cells. Hum. Gene Ther. Methods 28, 148–162 (2017).
Qu, W., Wang, M., Wu, Y. & Xu, R. Scalable downstream strategies for purification of recombinant adeno- associated virus vectors in light of the properties. Curr. Pharm. Biotechnol. 16, 684–695 (2015).
Qu, G. et al. Separation of adeno-associated virus type 2 empty particles from genome containing vectors by anion-exchange column chromatography. J. Virol. Methods 140, 183–192 (2007).
Lock, M., Alvira, M. R. & Wilson, J. M. Analysis of particle content of recombinant adeno-associated virus serotype 8 vectors by ion-exchange chromatography. Hum. Gene Ther. Methods 23, 56–64 (2012).
Nass, S. A. et al. Universal method for the purification of recombinant AAV vectors of differing serotypes. Mol. Ther. Methods Clin. Dev. 9, 33–46 (2018).
Donsante, A. et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science 317, 477 (2007). Although the consensus has shifted since its publication, this study is the first to demonstrate that AAV integration into the mouse Rian locus can upregulate proximal non-coding RNAs, leading to hepatocellular carcinoma.
Wang, P. R. et al. Induction of hepatocellular carcinoma by in vivo gene targeting. Proc. Natl Acad. Sci. USA 109, 11264–11269 (2012).
Zhong, L. et al. Recombinant adeno-associated virus integration sites in murine liver after ornithine transcarbamylase gene correction. Hum. Gene Ther. 24, 520–525 (2013).
Li, H. et al. Assessing the potential for AAV vector genotoxicity in a murine model. Blood 117, 3311–3319 (2011).
Chandler, R. J., LaFave, M. C., Varshney, G. K., Burgess, S. M. & Venditti, C. P. Genotoxicity in mice following AAV gene delivery: a safety concern for human gene therapy? Mol. Ther. 24, 198–201 (2016).
Chandler, R. J. et al. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J. Clin. Invest. 125, 870–880 (2015).
Gil-Farina, I. et al. Recombinant AAV integration is not associated with hepatic genotoxicity in nonhuman primates and patients. Mol. Ther. 24, 1100–1105 (2016).
Kaeppel, C. et al. A largely random AAV integration profile after LPLD gene therapy. Nat. Med. 19, 889–891 (2013).
Buning, H. & Schmidt, M. Adeno-associated vector toxicity-to be or not to be? Mol. Ther. 23, 1673–1675 (2015).
Srivastava, A. & Carter, B. J. AAV infection: protection from cancer. Hum. Gene Ther. 28, 323–327 (2017).
Emery, D. W., Yannaki, E., Tubb, J. & Stamatoyannopoulos, G. A chromatin insulator protects retrovirus vectors from chromosomal position effects. Proc. Natl Acad. Sci. USA 97, 9150–9155 (2000).
Liu, M. et al. Genomic discovery of potent chromatin insulators for human gene therapy. Nat. Biotechnol. 33, 198–203 (2015).
Hermonat, P. L. & Muzyczka, N. Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells. Proc. Natl Acad. Sci. USA 81, 6466–6470 (1984).
Tratschin, J. D., West, M. H., Sandbank, T. & Carter, B. J. A human parvovirus, adeno-associated virus, as a eucaryotic vector: transient expression and encapsidation of the procaryotic gene for chloramphenicol acetyltransferase. Mol. Cell. Biol. 4, 2072–2081 (1984).
Samulski, R. J., Chang, L. S. & Shenk, T. A recombinant plasmid from which an infectious adeno-associated virus genome can be excised in vitro and its use to study viral replication. J. Virol. 61, 3096–3101 (1987). This study is among the first to report cloning of the AAV genome into plasmids for the purposes of characterizing AAV replication.
McLaughlin, S. K., Collis, P., Hermonat, P. L. & Muzyczka, N. Adeno-associated virus general transduction vectors: analysis of proviral structures. J. Virol. 62, 1963–1973 (1988).
Samulski, R. J., Chang, L. S. & Shenk, T. Helper-free stocks of recombinant adeno-associated viruses: normal integration does not require viral gene expression. J. Virol. 63, 3822–3828 (1989).
Flotte, T. R. et al. Stable in vivo expression of the cystic fibrosis transmembrane conductance regulator with an adeno-associated virus vector. Proc. Natl Acad. Sci. USA 90, 10613–10617 (1993).
Kaplitt, M. G. et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat. Genet. 8, 148–154 (1994). This report is among the first to demonstrate that rAAVs can transduce cells of the CNS in vivo, hallmarking the potential for rAAVs as viable gene therapy vectors.
Flotte, T. et al. A phase I study of an adeno-associated virus-CFTR gene vector in adult CF patients with mild lung disease. Hum. Gene Ther. 7, 1145–1159 (1996). This study is the first clinical trial in humans for AAV-based gene therapy.
McCown, T. J., Xiao, X., Li, J., Breese, G. R. & Samulski, R. J. Differential and persistent expression patterns of CNS gene transfer by an adeno-associated virus (AAV) vector. Brain Res. 713, 99–107 (1996).
Kessler, P. D. et al. Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. Proc. Natl Acad. Sci. USA 93, 14082–14087 (1996). This report demonstrates the potential for AAV-based therapeutic transgene delivery to the muscle and for transformed muscle tissue as a viable target for ectopic expression of secreted proteins.
Xiao, X., Li, J. & Samulski, R. J. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J. Virol. 70, 8098–8108 (1996). This is the first publication that demonstrates successful long-term in vivo transduction of mammalian muscles by rAAVs.
Hauswirth, W. W. 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. 19, 979–990 (2008). References 313, 314 and 315 encompass a series of hallmark studies in human patients with LCA who were treated with rAAV2-hRPE65 vectors and showed improvement in visual sensitivity.
Bainbridge, J. W. et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N. Engl. J. Med. 358, 2231–2239 (2008).
Cideciyan, A. V. et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc. Natl Acad. Sci. USA 105, 15112–15117 (2008).