Atchison RW, Casto BC, Hammon WM. Adenovirus-associated defective virus particles. Science. 1965;149:754–6.
Google Scholar
Carter BJ. Adeno-associated virus and the development of adeno-associated virus vectors: a historical perspective. Mol Ther. 2004;10:981–9.
Google Scholar
Flotte TR, Berns KI. Adeno-associated virus: a ubiquitous commensal of mammals. Hum Gene Ther. 2005;16:401–7.
Google Scholar
Srivastava A, Lusby EW, Berns KI. Nucleotide sequence and organization of the adeno-associated virus 2 genome. J Virol. 1983;45:555–64.
Google Scholar
Muzyczka N. Use of adeno-associated virus as a general transduction vector for mammalian cells. Curr Top Microbiol Immunol. 1992;158:97–129.
Google Scholar
Muzyczka N, Berns KI. AAV’s golden jubilee. Mol Ther. 2015;23:807–8.
Google Scholar
Hastie E, Samulski RJ. Adeno-associated virus at 50: a golden anniversary of discovery, research, and gene therapy success-a personal perspective. Hum Gene Ther. 2015;26:257–65.
Google Scholar
High KA, Roncarolo MG. Gene Therapy. N Engl J Med. 2019;381:455–64.
Google Scholar
Wang D, Tai PWL, Gao GP. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019;18:358–78.
Google Scholar
Li C, Samulski RJ. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet. 2020;21:255–72.
Google Scholar
Bryant LM, Christopher DM, Giles AR, Hinderer C, Rodriguez JL, Smith JB, et al. Lessons learned from the clinical development and market authorization of Glybera. Human gene therapy. Clin Dev. 2013;24:55–64.
Google Scholar
Hoy SM. Onasemnogene abeparvovec: first global approval. Drugs. 2019;79:1255–62.
Google Scholar
Keeler AM, Flotte TR. Recombinant adeno-associated virus gene therapy in light of Luxturna (and Zolgensma and Glybera): where are we, and how did we get here? Annu Rev Virol. 2019;6:601–21.
Ciulla TA, Hussain RM, Berrocal AM, Nagiel A. Voretigene neparvovec-rzyl for Treatment of RPE65-mediated inherited retinal diseases: a model for ocular gene therapy development. Expert Opin Biol Ther. 2020;20:565–78.
Wilmott P, Lisowski L, Alexander IE, Logan GJ. A user’s guide to the inverted terminal repeats of adeno-associated virus. Hum Gene Ther Methods. 2019;30:206–13.
Google Scholar
Tai PWL. ITRs: The terminal frontier. Hum Gene Ther. 2020;31:143–4.
Google Scholar
Duan D, Yan Z, Yue Y, Engelhardt JF. Structural analysis of adeno-associated virus transduction intermediates. Virology. 1999;261:8–14.
Google Scholar
Kotterman MA, Schaffer DV. Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet. 2014;15:445–51.
Google Scholar
Wagner HJ, Weber W, Fussenegger M. Synthetic biology: emerging concepts to design and advance adeno-associated viral vectors for gene therapy. Adv Sci. 2021;8:2004018.
Lai Y, Duan D. Design of muscle gene therapy expression cassette. In: Duan D, Mendell JR, editors. Muscle Gene Therapy, Second edn. Springer Nature Switzerland; 2019.
Choi JH, Yu NK, Baek GC, Bakes J, Seo D, Nam HJ, et al. Optimization of AAV expression cassettes to improve packaging capacity and transgene expression in neurons. Mol Brain. 2014;7:17.
Google Scholar
Ryan JH, Zolotukhin S, Muzyczka N. Sequence requirements for binding of Rep68 to the adeno-associated virus terminal repeats. J Virol. 1996;70:1542–53.
Google Scholar
Brister JR, Muzyczka N. Rep-mediated nicking of the adeno-associated virus origin requires two biochemical activities, DNA helicase activity and transesterification. J Virol. 1999;73:9325–36.
Google Scholar
Brister JR, Muzyczka N. Mechanism of Rep-mediated adeno-associated virus origin nicking. J Virol. 2000;74:7762–71.
Google Scholar
Wang XS, Ponnazhagan S, Srivastava A. Rescue and replication of adeno-associated virus type 2 as well as vector DNA sequences from recombinant plasmids containing deletions in the viral inverted terminal repeats: selective encapsidation of viral genomes in progeny virions. J Virol. 1996;70:1668–77.
Google Scholar
Wang XS, Ponnazhagan S, Srivastava A. Rescue and replication signals of the adeno-associated virus 2 genome. J Mol Biol. 1995;250:573–80.
Google Scholar
Zhou QZ, Tian WH, Liu CG, Lian ZH, Dong XY, Wu XB. Deletion of the B-B′ and C-C′ regions of inverted terminal repeats reduces rAAV productivity but increases transgene expression. Sci Rep. 2017;7:5432.
Zhou X, Zeng X, Fan Z, Li C, McCown T, Samulski RJ, et al. Adeno-associated virus of a single-polarity DNA genome is capable of transduction in vivo. Mol Ther. 2008;16:494–9.
Google Scholar
Zhong L, Zhou X, Li Y, Qing K, Xiao X, Samulski RJ, et al. Single-polarity recombinant adeno-associated virus 2 vector-mediated transgene expression in vitro and in vivo: mechanism of transduction. Mol Ther. 2008;16:290–5.
Google Scholar
Wang Z, Ma HI, Li J, Sun L, Zhang J, Xiao X. Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo. Gene Ther. 2003;10:2105–11.
Google Scholar
McCarty DM, Fu H, Monahan PE, Toulson CE, Naik P, Samulski RJ. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther. 2003;10:2112–8.
Google Scholar
Ling C, Wang Y, Lu Y, Wang LN, Jayandharan GR, Aslanidi GV, et al. Enhanced transgene expression from recombinant single-stranded d-sequence-substituted adeno-associated virus vectors in human cell lines in vitro and in murine hepatocytes in vivo. J Virol. 2015;89:952–61.
Google Scholar
Wang XS, Khuntirat B, Qing K, Ponnazhagan S, Kube DM, Zhou S, et al. Characterization of wild-type adeno-associated virus type 2-like particles generated during recombinant viral vector production and strategies for their elimination. J Virol. 1998;72:5472–80.
Google Scholar
Weiner GJ, Liu HM, Wooldridge JE, Dahle CE, Krieg AM. Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization. Proc Natl Acad Sci USA. 1997;94:10833–7.
Google Scholar
Faust SM, Bell P, Cutler BJ, Ashley SN, Zhu Y, Rabinowitz JE, et al. CpG-depleted adeno-associated virus vectors evade immune detection. J Clin Invest. 2013;123:2994–3001.
Google Scholar
Wright JF. Codon modification and PAMPs in clinical AAV vectors: the tortoise or the hare? Mol Ther. 2020;28:701–3.
Google Scholar
Bertolini TB, Shirley JL, Zolotukhin I, Li X, Kaisho T, Xiao W, et al. Effect of CpG depletion of vector genome on CD8(+) T cell responses in AAV gene therapy. Front Immunol. 2021;12:672449.
Google Scholar
Konkle BA, Walsh CE, Escobar MA, Josephson NC, Young G, von Drygalski A, et al. BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression. Blood. 2021;137:763–74.
Google Scholar
Shin J-H, Hakim C, Zhang K, Duan D. Genotyping mdx, mdx3cv and mdx4cv mice by primer competition PCR. Muscle Nerve. 2011;43:283–6.
Google Scholar
Lai Y, Thomas GD, Yue Y, Yang HT, Li D, Long C, et al. Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy. J Clin Invest. 2009;119:624–35.
Google Scholar
Zhong L, Li B, Mah CS, Govindasamy L, Agbandje-McKenna M, Cooper M, 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. 2008;105:7827–32.
Google Scholar
Petrs-Silva H, Dinculescu A, Li Q, Min SH, Chiodo V, Pang JJ, et al. High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol Ther. 2009;17:463–71.
Google Scholar
Shin J-H, Yue Y, Duan D. Recombinant adeno-associated viral vector production and purification. Methods Mol Biol. 2012;798:267–84.
Google Scholar
Shin J-H, Pan X, Hakim CH, Yang HT, Yue Y, Zhang K, et al. Microdystrophin ameliorates muscular dystrophy in the canine model of Duchenne muscular dystrophy. Mol Ther. 2013;21:750–7.
Google Scholar
Tran NT, Heiner C, Weber K, Weiand M, Wilmot D, Xie J, et al. AAV-genome population sequencing of vectors packaging CRISPR components reveals design-influenced heterogeneity. Mol Ther-Meth Clin D. 2020;18:639–51.
Google Scholar
Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6.
Google Scholar
Lai Y, Yue Y, Duan D. Evidence for the failure of adeno-associated virus serotype 5 to package a viral genome > or = 8.2 kb. Mol Ther. 2010;18:75–9.
Google Scholar
Ghosh A, Yue Y, Lai Y, Duan D. A hybrid vector system expands aden-associated viral vector packaging capacity in a transgene independent manner. Mol Ther. 2008;16:124–30.
Google Scholar
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nature methods. 2012;9:676–82.
Google Scholar
Hakim CH, Li D, Duan D. Monitoring murine skeletal muscle function for muscle gene therapy. Methods Mol Biol. 2011;709:75–89.
Google Scholar
Hakim CH, Wasala NB, Pan X, Kodippili K, Yue Y, Zhang K, et al. A five-repeat micro-dystrophin gene ameliorated dystrophic phenotype in the severe DBA/2J-mdx model of Duchenne muscular dystrophy. Molecular therapy. Meth Clin Dev. 2017;6:216–30.
Google Scholar
Hakim CH, Wasala NB, Duan D. Evaluation of muscle function of the extensor digitorum longus muscle ex vivo and tibialis anterior muscle in situ in mice. J Vis Exp. 2013;72:e50183.
Mendez J, Keys A. Density and composition of mammalian muscle. Metabolism. 1960;9:184–8.
Google Scholar
Burkholder TJ, Fingado B, Baron S, Lieber RL. Relationship between muscle fiber types and sizes and muscle architectural properties in the mouse hindlimb. J Morphol. 1994;221:177–90.
Google Scholar
Berns KI. The unusual properties of the AAV inverted terminal repeat. Hum Gene Ther. 2020;31:518–23.
Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 2002;20:709–60.
Google Scholar
Ishii KJ, Akira S. Innate immune recognition of, and regulation by, DNA. Trends Immunol. 2006;27:525–32.
Google Scholar
Muramatsu S, Mizukami H, Young NS, Brown KE. Nucleotide sequencing and generation of an infectious clone of adeno-associated virus 3. Virology. 1996;221:208–17.
Google Scholar
Chiorini JA, Yang L, Liu Y, Safer B, Kotin RM. Cloning of adeno-associated virus type 4 (AAV4) and generation of recombinant AAV4 particles. J Virol. 1997;71:6823–33.
Google Scholar
Amiss TJ, McCarty DM, Skulimowski A, Samulski RJ. Identification and characterization of an adeno-associated virus integration site in CV-1 cells from the African green monkey. J Virol. 2003;77:1904–15.
Google Scholar
Im DS, Muzyczka N. Factors that bind to adeno-associated virus terminal repeats. J Virol. 1989;63:3095–104.
Google Scholar
Ashktorab H, Srivastava A. Identification of nuclear proteins that specifically interact with adeno-associated virus type 2 inverted terminal repeat hairpin DNA. J Virol. 1989;63:3034–9.
Google Scholar
Earley LF, Conatser LM, Lue VM, Dobbins AL, Li C, Hirsch ML, et al. Adeno-associated virus serotype-specific inverted terminal repeat sequence role in vector transgene expression. Hum Gene Ther. 2020;31:151–62.
Google Scholar
Grimm D, Pandey K, Nakai H, Storm TA, Kay MA. Liver transduction with recombinant adeno-associated virus is primarily restricted by capsid serotype not vector genotype. J Virol. 2006;80:426–39.
Google Scholar
Piovesan A, Pelleri MC, Antonaros F, Strippoli P, Caracausi M, Vitale L. On the length, weight and GC content of the human genome. BMC Res Notes. 2019;12:106.
Google Scholar
Duan D, Goemans N, Takeda S, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7:13.
Google Scholar
Samulski RJ, Muzyczka N. AAV-mediated gene therapy for research and therapeutic purposes. Annu Rev Virol. 2014;1:427–51.
Google Scholar
Ling C, Wang Y, Lu Y, Wang L, Jayandharan GR, Aslanidi GV, et al. The adeno-associated virus genome packaging puzzle. J Mol Genet Med. 2015;9:175.
Timpe J, Bevington J, Casper J, Dignam JD, Trempe JP. Mechanisms of adeno-associated virus genome encapsidation. Curr Gene Ther. 2005;5:273–84.
Google Scholar
Bennett A, Mietzsch M, Agbandje-McKenna M. Understanding capsid assembly and genome packaging for adeno-associated viruses. Fut Virol. 2017;12:283–97.
Google Scholar
King JA, Dubielzig R, Grimm D, Kleinschmidt JA. DNA helicase-mediated packaging of adeno-associated virus type 2 genomes into preformed capsids. Embo J. 2001;20:3282–91.
Google Scholar
Savy A, Dickx Y, Nauwynck L, Bonnin D, Merten OW, Galibert L. Impact of inverted terminal repeat integrity on rAAV8 production using the Baculovirus/Sf9 cells system. Hum Gene Ther Meth. 2017;28:277–89.
Google Scholar
Duan D, Sharma P, Yang J, Yue Y, Dudus L, Zhang Y, et al. Circular intermediates of recombinant adeno-associated virus have defined structural characteristics responsible for long term episomal persistence in muscle. J. Virol. 1998;72:8568–77.
Google Scholar
Duan D, Sharma P, Dudus L, Zhang Y, Sanlioglu S, Yan Z, et al. Formation of adeno-associated virus circular genomes is differentially regulated by adenovirus E4 ORF6 and E2a gene expression. J Virol. 1999;73:161–9.
Google Scholar
Yan Z, Zak R, Zhang Y, Engelhardt JF. Inverted terminal repeat sequences are important for intermolecular recombination and circularization of adeno-associated virus genomes. J Virol. 2005;79:364–79.
Google Scholar
Samulski RJ, Chang LS, 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. 1987;61:3096–101.
Google Scholar
Tai PWL, Xie J, Fong K, Seetin M, Heiner C, Su Q, et al. Adeno-associated virus genome population sequencing achieves full vector genome resolution and reveals human-vector chimeras. Molecular therapy. Meth Clin Dev. 2018;9:130–41.
Google Scholar
Xiao W, Chirmule N, Berta SC, McCullough B, Gao G, Wilson JM. Gene therapy vectors based on adeno-associated virus type 1. J Virol. 1999;73:3994–4003.
Google Scholar
Lusby E, Fife KH, Berns KI. Nucleotide sequence of the inverted terminal repetition in adeno- associated virus DNA. J Virol. 1980;34:402–9.
Google Scholar
Rutledge EA, Halbert CL, Russell DW. Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J Virol. 1998;72:309–19.
Google Scholar
Chiorini JA, Kim F, Yang L, Kotin RM. Cloning and characterization of adeno-associated virus type 5. J Virol. 1999;73:1309–19.
Google Scholar
Estevez C, Villegas P. Sequence analysis, viral rescue from infectious clones and generation of recombinant virions of the avian adeno-associated virus. Virus Res. 2004;105:195–208.
Google Scholar
Bossis I, Chiorini JA. Cloning of an avian adeno-associated virus (AAAV) and generation of recombinant AAAV particles. J Virol. 2003;77:6799–810.
Google Scholar
Schmidt M, Katano H, Bossis I, Chiorini JA. Cloning and characterization of a bovine adeno-associated virus. J Virol. 2004;78:6509–16.
Google Scholar
Grimm D, Kay MA, Kleinschmidt JA. Helper virus-free, optically controllable, and two-plasmid-based production of adeno-associated virus vectors of serotypes 1 to 6. Mol Ther. 2003;7:839–50.
Google Scholar
Halbert CL, Allen JM, Miller AD. Adeno-associated virus type 6 (aav6) vectors mediate efficient transduction of airway epithelial cells in mouse lungs compared to that of aav2 vectors. J Virol. 2001;75:6615–24.
Google Scholar
Chejanovsky N, Carter BJ. Mutagenesis of an AUG codon in the adeno-associated virus rep gene: effects on viral DNA replication. Virology. 1989;173:120–8.
Google Scholar
Yew NS, Cheng SH. Reducing the immunostimulatory activity of CpG-containing plasmid DNA vectors for non-viral gene therapy. Expert Opinion Drug Deliv. 2004;1:115–25.
Google Scholar
Hyde SC, Pringle IA, Abdullah S, Lawton AE, Davies LA, Varathalingam A, et al. CpG-free plasmids confer reduced inflammation and sustained pulmonary gene expression. Nat Biotechnol. 2008;26:549–51.
Google Scholar
Duan D, Systemic AAV. Micro-dystrophin gene therapy for duchenne muscular dystrophy. Mol Ther. 2018;26:2337–56.
Google Scholar

