Adeno-Associated Virus: The Naturally Occurring Virus Versus the Recombinant Vector

Manno CS , Pierce GF , Arruda VR , et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med, 2006; 12:342–347.

Zhong L , Zhao W , Wu J , et al. A dual role of EGFR protein tyrosine kinase signaling in ubiquitination of AAV2 capsids and viral second-strand DNA synthesis. Mol Ther, 2007; 15:1323–1330.

Duan D , Yue Y , Yan Z , et al. Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus. J Clin Invest, 2000; 105:1573–1587.

Zhong L , Li B , Mah CS , 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 U S A, 2008; 105:7827–7832.

Markusic DM , Herzog RW , Aslanidi GV , et al. High-efficiency transduction and correction of murine hemophilia B using AAV2 vectors devoid of multiple surface-exposed tyrosines. Mol Ther, 2010; 18:2048–2056.

Martino AT , Basner-Tschakarjan E , Markusic DM , et al. Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8⁺ T cells. Blood, 2013; 121:2224–2233.

Aslanidi GV , Rivers AE , Ortiz L , et al. Optimization of the capsid of recombinant adeno-associated virus 2 (AAV2) vectors: the final threshold?. PLoS One, 2013; 8:e59142.

Li B , Ma W , Ling C , et al. Site-directed mutagenesis of surface-exposed lysine residues leads to improved transduction by AAV2, but not AAV8, vectors in murine hepatocytes in vivo . Hum Gene Ther Methods, 2015; 26:211–220.

Guy J ; National Eye Institute. Safety study of an adeno-associated virus vector for gene therapy of Leber's hereditary optic neuropathy (LHON). In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine. 2014– [cited 2015 Dec 16]. Available from: https://clinicaltrials.gov/ct2/show/NCT02161380 [NLM Identifier: NCT02161380].

Applied Genetic Technologies Corp.. Safety and efficacy of rAAV-hRS1 in patients with X-linked retinoschisis (XLRS). In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine. 2015– [cited 2015 Dec 16]. Available from: https://clinicaltrials.gov/ct2/show/NCT02416622 [NLM Identifier: NCT02416622].

Applied Genetic Technologies Corp.. Safety and efficacy trial of AAV gene therapy in patients with CNGB3 achromatopsia. In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine. 2015- [cited 2015 Nov 5]. Available from: https://clinicaltrials.gov/cL2/show/NCT02599922 [NLM Identifier: NCT02599922].

Fisher KJ , Gao GP , Weitzman MD , et al. Transduction with recombinant adeno-associated virus for gene therapy is limited by leading-strand synthesis. J Virol, 1996; 70:520–532.

Ferrari FK , Samulski T , Shenk T , et al. Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol, 1996; 70:3227–3234.

Zhong L , Zhou X , Li Y , et al. Single-polarity recombinant adeno-associated virus 2 vector-mediated transgene expression in vitro and in vivo: mechanism of transduction. Mol Ther, 2008; 16:290–295.

Zhou X , Zeng X , Fan Z , et al. Adeno-associated virus of a single-polarity DNA genome is capable of transduction in vivo . Mol Ther, 2008; 16:494–499.

Ponnazhagan S , Mukherjee P , Yoder MC , et al. Adeno-associated virus 2-mediated gene transfer in vivo: organ-tropism and expression of transduced sequences in mice. Gene, 1997; 190:203–210.

Snyder RO , Miao CH , Patijn GA , et al. Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors. Nat Genet, 1997; 16:270–276.

Qing K , Khuntirat B , Mah C , et al. Adeno-associated virus type 2-mediated gene transfer: correlation of tyrosine phosphorylation of the cellular single-stranded D sequence-binding protein with transgene expression in human cells in vitro and murine tissues in vivo . J Virol, 1998; 72:1593–1599.

McCarty DM , Monahan PE , and Samulski RJ . Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther, 2001; 8:1248–1254.

Nathwani AC , Tuddenham EG , Rangarajan S , et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med, 2011; 365:2357–2365.

Nathwani AC , Reiss UM , Tuddenham EG , et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med, 2014; 371:1994–2004.

Lisowski L , Dane AP , Chu K , et al. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature, 2014; 506:382–386.

Li S , Ling C , Zhong L , et al. Efficient and targeted transduction of nonhuman primate liver with systemically delivered optimized AAV3B vectors. Mol Ther, 2015; 23:1867–1876.

Wang L , Bell P , Somanathan S , et al. Comparative study of liver gene transfer with AAV vectors based on natural and engineered AAV capsids. Mol Ther, 2015; 23:1877–1887.

Bainbridge JW , Smith AJ , Barker SS , et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med, 2008; 358:2231–2239.

Maguire AM , Simonelli F , Pierce EA , et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med, 2008; 358:2240–2248.

Cideciyan AV , Aleman TS , Boye SL , et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A, 2008; 105:15112–15117.

Hauswirth WW , Aleman TS , Kaushal S , 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, 2008; 19:979–990.

Stroes ES , Nierman MC , Meulenberg JJ , et al. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol, 2008; 28:2303–2304.

Hwu WL , Muramatsu S , Tseng SH , et al. Gene therapy for aromatic l-amino acid decarboxylase deficiency. Sci Transl Med, 2012; 4:134ra61.

MacLaren RE , Groppe M , Barnard AR , et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet, 2014; 383:1129–1137.

Qing K , Wang XS , Kube DM , et al. Role of tyrosine phosphorylation of a cellular protein in adeno-associated virus 2-mediated transgene expression. Proc Natl Acad Sci U S A, 1997; 94:10879–10884.

Mah C , Qing K , Khuntirat B , et al. Adeno-associated virus type 2-mediated gene transfer: role of epidermal growth factor receptor protein tyrosine kinase in transgene expression. J Virol, 1998; 72:9835–9843.

Qing K , Li W , Zhong L , et al. Adeno-associated virus type 2-mediated gene transfer: role of cellular T-cell protein tyrosine phosphatase in transgene expression in established cell lines in vitro and transgenic mice in vivo . J Virol, 2003; 77:2741–2746.

Zhong L , Li W , Yang Z , et al. Improved transduction of primary murine hepatocytes by recombinant adeno-associated virus 2 vectors in vivo . Gene Ther, 2004; 11:1165–1169.

Zhong L , Chen L , Li Y , et al. Self-complementary adeno-associated virus 2 (AAV)-T cell protein tyrosine phosphatase vectors as helper viruses to improve transduction efficiency of conventional single-stranded AAV vectors in vitro and in vivo . Mol Ther, 2004; 10:950–957.

Jayandharan GR , Zhong L , Li B , et al. Strategies for improving the transduction efficiency of single-stranded adeno-associated virus vectors in vitro and in vivo . Gene Ther, 2008; 15:1287–1293.

Jayandharan GR , Zhong L , Sack BK , et al. Optimized adeno-associated virus (AAV)-protein phosphatase-5 helper viruses for efficient liver transduction by single-stranded AAV vectors: therapeutic expression of factor IX at reduced vector doses. Hum Gene Ther, 2010; 21:271–283.

Wang XS , Ponnazhagan S , and Srivastava A . Rescue and replication signals of the adeno-associated virus 2 genome. J Mol Biol, 1995; 250:573–580.

Wang XS , Ponnazhagan S , and 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; 70:1668–1677.

Ling C , Wang Y , Lu Y , et al. The adeno-associated virus genome packaging puzzle. J Mol Genet Med, 2015; 9: 175.

Jayandharan G , Aslanidi G , Martino AT , et al. Activation of the NF-κB pathway by adeno-associated virus (AAV) vectors and its implications in immune response and gene therapy. Proc Natl Acad Sci U S A, 2011; 108:3743–3748.

Ling C , Wang Y , Lu Y , 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; 89:952–961.

Naldini L . Gene therapy returns to centre stage. Nature, 2015; 526:351–360.