AAV-Mediated Gene Therapy for Research and Therapeutic Purposes.

Adeno-associated virus (AAV) is a small, nonenveloped virus that was adapted 30 years ago for use as a gene transfer vehicle. It is capable of transducing a wide range of species and tissues in vivo with no evidence of toxicity, and it generates relatively mild innate and adaptive immune responses. We review the basic biology of AAV, the history of progress in AAV vector technology, and some of the clinical and research applications where AAV has shown success.

[1]  N. Osterrieder,et al.  Herpesvirus Genome Integration into Telomeric Repeats of Host Cell Chromosomes. , 2014, Annual review of virology.

[2]  I. Cristea,et al.  The Impact of Mass Spectrometry-Based Proteomics on Fundamental Discoveries in Virology. , 2014, Annual review of virology.

[3]  S. Weger,et al.  OneBac: platform for scalable and high-titer production of adeno-associated virus serotype 1-12 vectors for gene therapy. , 2014, Human gene therapy.

[4]  W. Hauswirth,et al.  Dual adeno-associated virus vectors result in efficient in vitro and in vivo expression of an oversized gene, MYO7A. , 2014, Human gene therapy methods.

[5]  Hong Qian,et al.  Statistics and Related Topics in Single-Molecule Biophysics. , 2014, Annual review of statistics and its application.

[6]  N. Muzyczka,et al.  Adeno-Associated Virus Capsid Proteins May Play a Role in Transcription and Second-Strand Synthesis of Recombinant Genomes , 2013, Journal of Virology.

[7]  M. Agbandje-McKenna,et al.  Mapping the AAV Capsid Host Antibody Response toward the Development of Second Generation Gene Delivery Vectors , 2013, Front. Immunol..

[8]  M. Lindstrom,et al.  Gene delivery of Homer1c rescues spatial learning in a rodent model of cognitive aging , 2013, Neurobiology of Aging.

[9]  H. Sweeney,et al.  Enhancing the utility of adeno-associated virus gene transfer through inducible tissue-specific expression. , 2013, Human gene therapy methods.

[10]  J. F. Wright,et al.  Overcoming Preexisting Humoral Immunity to AAV Using Capsid Decoys , 2013, Science Translational Medicine.

[11]  S. Deventer,et al.  Mir‐142‐3p target sequences reduce transgene‐directed immunogenicity following intramuscular adeno‐associated virus 1 vector‐mediated gene delivery , 2013, The journal of gene medicine.

[12]  Josh Tycko,et al.  Lessons learned from the clinical development and market authorization of Glybera. , 2013, Human gene therapy. Clinical development.

[13]  W. Hauswirth,et al.  Targeting Photoreceptors via Intravitreal Delivery Using Novel, Capsid-Mutated AAV Vectors , 2013, PloS one.

[14]  W. Hauswirth,et al.  A comprehensive review of retinal gene therapy. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[15]  R. Bartus,et al.  Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating “clinical proof-of-concept” for AAV-neurturin (CERE-120) in Parkinson's disease , 2013, Neurobiology of Aging.

[16]  R. Hajjar,et al.  Gene Therapy for Heart Failure: Where Do We Stand? , 2013, Current Cardiology Reports.

[17]  D. Shera,et al.  Long-Term Follow-Up After Gene Therapy for Canavan Disease , 2012, Science Translational Medicine.

[18]  K. L. La Perle,et al.  Patterns of scAAV vector insertion associated with oncogenic events in a mouse model for genotoxicity. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[19]  R. Samulski,et al.  Cytoplasmic Trafficking, Endosomal Escape, and Perinuclear Accumulation of Adeno-Associated Virus Type 2 Particles Are Facilitated by Microtubule Network , 2012, Journal of Virology.

[20]  R. Klein,et al.  The advent of AAV9 expands applications for brain and spinal cord gene delivery , 2012, Expert opinion on biological therapy.

[21]  David V Schaffer,et al.  The AAV Vector Toolkit: Poised at the Clinical Crossroads. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[22]  D. Schaffer,et al.  Directed evolution of novel adeno-associated viruses for therapeutic gene delivery , 2012, Gene Therapy.

[23]  M. Nonnenmacher,et al.  Intracellular transport of recombinant adeno-associated virus vectors , 2012, Gene Therapy.

[24]  Kathleen A. Marshall,et al.  AAV2 Gene Therapy Readministration in Three Adults with Congenital Blindness , 2012, Science Translational Medicine.

[25]  J. Grieger,et al.  Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[26]  T. Foster,et al.  Enhanced expression of Pctk1, Tcf12 and Ccnd1 in hippocampus of rats: Impact on cognitive function, synaptic plasticity and pathology , 2012, Neurobiology of Learning and Memory.

[27]  M. R. Delgado Alvira,et al.  Analysis of particle content of recombinant adeno-associated virus serotype 8 vectors by ion-exchange chromatography. , 2012, Human gene therapy methods.

[28]  Pratima Chowdary,et al.  Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. , 2011, The New England journal of medicine.

[29]  M. Nonnenmacher,et al.  Adeno-associated virus 2 infection requires endocytosis through the CLIC/GEEC pathway. , 2011, Cell host & microbe.

[30]  G. Rogers,et al.  Innate Immune Responses to AAV Vectors , 2011, Front. Microbio..

[31]  R. Kuhn,et al.  Current opinion in virology: structural virology. , 2011, Current opinion in virology.

[32]  E. Surace,et al.  MicroRNA-Restricted Transgene Expression in the Retina , 2011, PloS one.

[33]  H. Morizono,et al.  Adeno-Associated Virus Antibody Profiles in Newborns, Children, and Adolescents , 2011, Clinical and Vaccine Immunology.

[34]  Lief E. Fenno,et al.  The development and application of optogenetics. , 2011, Annual review of neuroscience.

[35]  T. Flotte,et al.  Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results. , 2011, Human gene therapy.

[36]  R. Kotin.  Large-scale recombinant adeno-associated virus production. , 2011, Human molecular genetics.

[37]  H. Fechner,et al.  microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors , 2011, Gene Therapy.

[38]  T. Flotte,et al.  Preclinical evaluation of a recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin made using a recombinant herpes simplex virus production method. , 2011, Human gene therapy.

[39]  H. Fu,et al.  Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[40]  Juan Li,et al.  Liver-specific microRNA-122 target sequences incorporated in AAV vectors efficiently inhibits transgene expression in the liver , 2010, Gene Therapy.

[41]  R. Samulski,et al.  Chapter 17:Viral Vectors for Gene Delivery , 2010 .

[42]  Gavin Rumbaugh,et al.  Myosin IIb Regulates Actin Dynamics during Synaptic Plasticity and Memory Formation , 2010, Neuron.

[43]  R. Mandel,et al.  In Vivo RNAi-Mediated α-Synuclein Silencing Induces Nigrostriatal Degeneration. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[44]  Songtao Li,et al.  Hydrostatic Isolated Limb Perfusion with Adeno-associated Virus Vectors Enhances Correction of Skeletal Muscle in Pompe Disease , 2010, Gene Therapy.

[45]  J. Kleinschmidt,et al.  A viral assembly factor promotes AAV2 capsid formation in the nucleolus , 2010, Proceedings of the National Academy of Sciences.

[46]  R. Mandel.  CERE-110, an adeno-associated virus-based gene delivery vector expressing human nerve growth factor for the treatment of Alzheimer's disease. , 2010, Current opinion in molecular therapeutics.

[47]  W. Jagust,et al.  Safety and tolerability of putaminal AADC gene therapy for Parkinson disease , 2009, Neurology.

[48]  R. Mandel,et al.  Tight Long-term dynamic doxycycline responsive nigrostriatal GDNF using a single rAAV vector. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[49]  R. Kotin,et al.  A simplified baculovirus-AAV expression vector system coupled with one-step affinity purification yields high-titer rAAV stocks from insect cells. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[50]  Lili Wang,et al.  Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy , 2009, Proceedings of the National Academy of Sciences.

[51]  B. Byrne,et al.  Tolerance Induction to Cytoplasmic β-Galactosidase by Hepatic AAV Gene Transfer — Implications for Antigen Presentation and Immunotoxicity , 2009, PloS one.

[52]  Xiaopei Huang,et al.  The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice. , 2009, The Journal of clinical investigation.

[53]  R. Kotin,et al.  Producing recombinant adeno-associated virus in foster cells: overcoming production limitations using a baculovirus-insect cell expression strategy. , 2009, Human gene therapy.

[54]  B. Byrne,et al.  Large-scale adeno-associated viral vector production using a herpesvirus-based system enables manufacturing for clinical studies. , 2009, Human gene therapy.

[55]  R. Peluso,et al.  Manufacturing recombinant adeno-associated viral vectors from producer cell clones. , 2009, Human gene therapy.

[56]  J. F. Wright,et al.  Transient transfection methods for clinical adeno-associated viral vector production. , 2009, Human gene therapy.

[57]  G. Veres,et al.  Scalable recombinant adeno-associated virus production using recombinant herpes simplex virus type 1 coinfection of suspension-adapted mammalian cells. , 2009, Human gene therapy.

[58]  A. Epstein,et al.  Definition of Herpes Simplex Virus Type 1 Helper Activities for Adeno-Associated Virus Early Replication Events , 2009, PLoS pathogens.

[59]  W. Hauswirth,et al.  High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[60]  R. Mandel,et al.  Striatal readministration of rAAV vectors reveals an immune response against AAV2 capsids that can be circumvented. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[61]  James M. Wilson,et al.  Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. , 2009, The Journal of infectious diseases.

[62]  R. Samulski,et al.  Enhancement of Adeno-Associated Virus Infection by Mobilizing Capsids into and Out of the Nucleolus , 2008, Journal of Virology.

[63]  Philip R. Johnson,et al.  Infectious Molecular Clones of Adeno-Associated Virus Isolated Directly from Human Tissues , 2008, Journal of Virology.

[64]  W. Hauswirth,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. , 2008, Human gene therapy.

[65]  D. Mccarty.  Self-complementary AAV vectors; advances and applications. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[66]  Edwin M Stone,et al.  Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics , 2008, Proceedings of the National Academy of Sciences.

[67]  B. Wang,et al.  Protein trans-splicing as a means for viral vector-mediated in vivo gene therapy. , 2008, Human gene therapy.

[68]  N. Sharpless,et al.  Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[69]  W. Hauswirth,et al.  Targeting gene expression to cones with human cone opsin promoters in recombinant AAV , 2008, Gene Therapy.

[70]  W. Hauswirth,et al.  Targeting gene expression to cones with human cone opsin promoters in recombinant AAV , 2008, Gene Therapy.

[71]  C. von Kalle,et al.  Adeno-Associated Virus Vector Genomes Persist as Episomal Chromatin in Primate Muscle , 2008, Journal of Virology.

[72]  N. Muzyczka,et al.  Next generation of adeno-associated virus 2 vectors: Point mutations in tyrosines lead to high-efficiency transduction at lower doses , 2008, Proceedings of the National Academy of Sciences.

[73]  Nick Tyler,et al.  Effect of gene therapy on visual function in Leber's congenital amaurosis. , 2008, The New England journal of medicine.

[74]  Kathleen A. Marshall,et al.  Safety and efficacy of gene transfer for Leber's congenital amaurosis. , 2008, The New England journal of medicine.

[75]  K. High,et al.  AAV-mediated gene transfer for the treatment of hemophilia B: problems and prospects , 2008, Gene Therapy.

[76]  Theresa A. Storm,et al.  In Vitro and In Vivo Gene Therapy Vector Evolution via Multispecies Interbreeding and Retargeting of Adeno-Associated Viruses , 2008, Journal of Virology.

[77]  R. Samulski,et al.  Adeno-associated virus of a single-polarity DNA genome is capable of transduction in vivo. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[78]  R. Samulski,et al.  Single-polarity recombinant adeno-associated virus 2 vector-mediated transgene expression in vitro and in vivo: mechanism of transduction. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[79]  N. Muzyczka,et al.  Complete In Vitro Reconstitution of Adeno-Associated Virus DNA Replication Requires the Minichromosome Maintenance Complex Proteins , 2007, Journal of Virology.

[80]  M. Weitzman,et al.  The Mre11/Rad50/Nbs1 Complex Limits Adeno-Associated Virus Transduction and Replication , 2007, Journal of Virology.

[81]  Theresa A. Storm,et al.  DNA Palindromes with a Modest Arm Length of ≳20 Base Pairs Are a Significant Target for Recombinant Adeno-Associated Virus Vector Integration in the Liver, Muscles, and Heart in Mice , 2007, Journal of Virology.

[82]  Daniel G. Miller,et al.  AAV Vector Integration Sites in Mouse Hepatocellular Carcinoma , 2007, Science.

[83]  J. Grieger,et al.  Surface-Exposed Adeno-Associated Virus Vp1-NLS Capsid Fusion Protein Rescues Infectivity of Noninfectious Wild-Type Vp2/Vp3 and Vp3-Only Capsids but Not That of Fivefold Pore Mutant Virions , 2007, Journal of Virology.

[84]  P. Laipis,et al.  PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pah enu2 mice , 2007, Brain Research.

[85]  J. Kleinschmidt,et al.  Isolation of targeted AAV2 vectors from novel virus display libraries , 2006, The journal of gene medicine.

[86]  J. Kleinschmidt,et al.  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 , 2006, Journal of Virology.

[87]  D. Schaffer,et al.  Construction of diverse adeno-associated viral libraries for directed evolution of enhanced gene delivery vehicles , 2006, Nature Protocols.

[88]  E. Furth,et al.  Analysis of tumors arising in male B6C3F1 mice with and without AAV vector delivery to liver. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[89]  N. Stow,et al.  Role of the Herpes Simplex Virus Helicase-Primase Complex during Adeno-Associated Virus DNA Replication , 2006, Journal of Virology.

[90]  J. Grieger,et al.  Separate Basic Region Motifs within the Adeno-Associated Virus Capsid Proteins Are Essential for Infectivity and Assembly , 2006, Journal of Virology.

[91]  R. Kotin,et al.  Scalable Generation of High-Titer Recombinant Adeno-Associated Virus Type 5 in Insect Cells , 2006, Journal of Virology.

[92]  D. Schaffer,et al.  Directed evolution of adeno-associated virus yields enhanced gene delivery vectors , 2006, Nature Biotechnology.

[93]  B. Byrne,et al.  Successful production of pseudotyped rAAV vectors using a modified baculovirus expression system. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[94]  W. Hauswirth,et al.  Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[95]  Lili Wang,et al.  No evidence for tumorigenesis of AAV vectors in a large-scale study in mice. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[96]  Brian M. Suzuki,et al.  AAV2-mediated gene delivery to monkey putamen: Evaluation of an infusion device and delivery parameters , 2005, Experimental Neurology.

[97]  K. Stieger,et al.  Long-term doxycycline-regulated transgene expression in the retina of nonhuman primates following subretinal injection of recombinant AAV vectors. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[98]  J. Kleinschmidt,et al.  Mutational Analysis of Narrow Pores at the Fivefold Symmetry Axes of Adeno-Associated Virus Type 2 Capsids Reveals a Dual Role in Genome Packaging and Activation of Phospholipase A2 Activity , 2005, Journal of Virology.

[99]  M. R. Delgado Alvira,et al.  Clades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues , 2004, Journal of Virology.

[100]  N. Muzyczka,et al.  Adeno-Associated Virus Type 2 VP2 Capsid Protein Is Nonessential and Can Tolerate Large Peptide Insertions at Its N Terminus , 2004, Journal of Virology.

[101]  A. Benraiss,et al.  Identification of a replication‐defective herpes simplex virus for recombinant adeno‐associated virus type 2 (rAAV2) particle assembly using stable producer cell lines , 2004, The journal of gene medicine.

[102]  C. Lilley,et al.  The Mre11 complex is required for ATM activation and the G2/M checkpoint , 2003, The EMBO journal.

[103]  J. Kleinschmidt,et al.  Identification of a Heparin-Binding Motif on Adeno-Associated Virus Type 2 Capsids , 2003, Journal of Virology.

[104]  Wadih Arap,et al.  Random peptide libraries displayed on adeno-associated virus to select for targeted gene therapy vectors , 2003, Nature Biotechnology.

[105]  Anders Björklund,et al.  Modeling CNS neurodegeneration by overexpression of disease-causing proteins using viral vectors , 2003, Trends in Neurosciences.

[106]  N. Muzyczka,et al.  Identification of Amino Acid Residues in the Capsid Proteins of Adeno-Associated Virus Type 2 That Contribute to Heparan Sulfate Proteoglycan Binding , 2003, Journal of Virology.

[107]  Philip R. Johnson,et al.  Genetic Fate of Recombinant Adeno-Associated Virus Vector Genomes in Muscle , 2003, Journal of Virology.

[108]  A. Björklund,et al.  Nigrostriatal α-synucleinopathy induced by viral vector-mediated overexpression of human α-synuclein: A new primate model of Parkinson's disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[109]  A. Salvetti,et al.  Evidence for Packaging of rep-cap Sequences into Adeno-Associated Virus (AAV) Type 2 Capsids in the Absence of Inverted Terminal Repeats: a Model for Generation of rep-Positive AAV Particles , 2003, Journal of Virology.

[110]  W. Hauswirth,et al.  Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. , 2002, Methods.

[111]  Lili Wang,et al.  Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[112]  Daniel F. Lackner,et al.  Studies of the Mechanism of Transactivation of the Adeno-Associated Virus p19 Promoter by Rep Protein , 2002, Journal of Virology.

[113]  M. S. Chapman,et al.  The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[114]  B. Byrne,et al.  Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[115]  M. Hallek,et al.  The VP1 capsid protein of adeno-associated virus type 2 is carrying a phospholipase A2 domain required for virus infectivity. , 2002, The Journal of general virology.

[116]  R. Linden,et al.  Novel cis-Acting Replication Element in the Adeno-Associated Virus Type 2 Genome Is Involved in Amplification of Integrated rep-cap Sequences , 2001, Journal of Virology.

[117]  J. Hansen,et al.  Infection of purified nuclei by adeno-associated virus 2. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[118]  James M. Wilson,et al.  A single-step affinity column for purification of serotype-5 based adeno-associated viral vectors. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[119]  T. Flotte,et al.  Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors , 2001, Gene Therapy.

[120]  D. McCarty,et al.  Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis , 2001, Gene Therapy.

[121]  Theresa A. Storm,et al.  Extrachromosomal Recombinant Adeno-Associated Virus Vector Genomes Are Primarily Responsible for Stable Liver Transduction In Vivo , 2001, Journal of Virology.

[122]  D. Grimm,et al.  DNA helicase‐mediated packaging of adeno‐associated virus type 2 genomes into preformed capsids , 2001, The EMBO journal.

[123]  Arun Srivastava,et al.  Adeno-Associated Virus Type 2-Mediated Gene Transfer: Altered Endocytic Processing Enhances Transduction Efficiency in Murine Fibroblasts , 2001, Journal of Virology.

[124]  T. Flotte,et al.  Effect Of DNA-dependent protein kinase on the molecular fate of the rAAV2 genome in skeletal muscle , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[125]  O. Danos,et al.  Intracellular Trafficking of Adeno-Associated Virus Vectors: Routing to the Late Endosomal Compartment and Proteasome Degradation , 2001, Journal of Virology.

[126]  H. Avet-Loiseau,et al.  Characterization of Adenovirus-Induced Inverted Terminal Repeat-Independent Amplification of Integrated Adeno-Associated Virus rep-cap Sequences , 2001, Journal of Virology.

[127]  M. Weitzman,et al.  A Functional Complex of Adenovirus Proteins E1B-55kDa and E4orf6 Is Necessary To Modulate the Expression Level of p53 but Not Its Transcriptional Activity , 2000, Journal of Virology.

[128]  Theresa A. Storm,et al.  Recruitment of Single-Stranded Recombinant Adeno-Associated Virus Vector Genomes and Intermolecular Recombination Are Responsible for Stable Transduction of Liver In Vivo , 2000, Journal of Virology.

[129]  R. Haberman,et al.  Novel Transcriptional Regulatory Signals in the Adeno-Associated Virus Terminal Repeat A/D Junction Element , 2000, Journal of Virology.

[130]  T. Conlon,et al.  Mutational Analysis of the Adeno-Associated Virus Type 2 (AAV2) Capsid Gene and Construction of AAV2 Vectors with Altered Tropism , 2000, Journal of Virology.

[131]  N. Muzyczka,et al.  Mechanism of Rep-Mediated Adeno-Associated Virus Origin Nicking , 2000, Journal of Virology.

[132]  Theresa A. Storm,et al.  Increasing the size of rAAV-mediated expression cassettes in vivo by intermolecular joining of two complementary vectors , 2000, Nature Biotechnology.

[133]  R. Samulski,et al.  Infectious Entry Pathway of Adeno-Associated Virus and Adeno-Associated Virus Vectors , 2000, Journal of Virology.

[134]  R. Chen,et al.  Gene transfer into the CNS using recombinant adeno-associated virus: analysis of vector DNA forms resulting in sustained expression. , 1999, Journal of drug targeting.

[135]  S. Weger,et al.  Adeno-Associated Virus Type 2 Protein Interactions: Formation of Pre-Encapsidation Complexes , 1999, Journal of Virology.

[136]  N. Muzyczka,et al.  Rep-Mediated Nicking of the Adeno-Associated Virus Origin Requires Two Biochemical Activities, DNA Helicase Activity and Transesterification , 1999, Journal of Virology.

[137]  R. Levinsky,et al.  High-titer recombinant adeno-associated virus production from replicating amplicons and herpes vectors deleted for glycoprotein H. , 1999, Human gene therapy.

[138]  G. Deléage,et al.  Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2 , 1999, Nature Medicine.

[139]  D. Grimm,et al.  Titration of AAV-2 particles via a novel capsid ELISA: packaging of genomes can limit production of recombinant AAV-2 , 1999, Gene Therapy.

[140]  B. Byrne,et al.  Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield , 1999, Gene Therapy.

[141]  T. Daly,et al.  Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[142]  D. Bohl,et al.  Structure of Adeno-Associated Virus Vector DNA following Transduction of the Skeletal Muscle , 1999, Journal of Virology.

[143]  T. Flotte,et al.  Safety and Biological Efficacy of an Adeno‐Associated Virus Vector–Cystic Fibrosis Transmembrane Regulator (AAV‐CFTR) in the Cystic Fibrosis Maxillary Sinus , 1999, The Laryngoscope.

[144]  D. Grimm,et al.  Novel tools for production and purification of recombinant adenoassociated virus vectors. , 1998, Human gene therapy.

[145]  S. Leff,et al.  Regulation of gene expression in vivo following transduction by two separate rAAV vectors , 1998, Nature Biotechnology.

[146]  L. Villarreal,et al.  Adeno-associated virus vectors can be efficiently produced without helper virus , 1998, Gene Therapy.

[147]  R. Kotin,et al.  The Rep52 Gene Product of Adeno-Associated Virus Is a DNA Helicase with 3′-to-5′ Polarity , 1998, Journal of Virology.

[148]  B. Stillman,et al.  Cellular Proteins Required for Adeno-Associated Virus DNA Replication in the Absence of Adenovirus Coinfection , 1998, Journal of Virology.

[149]  R. Samulski,et al.  Production of High-Titer Recombinant Adeno-Associated Virus Vectors in the Absence of Helper Adenovirus , 1998, Journal of Virology.

[150]  F. Dean,et al.  Role of the Adenovirus DNA-Binding Protein in In Vitro Adeno-Associated Virus DNA Replication , 1998, Journal of Virology.

[151]  D. Russell,et al.  Infectious Clones and Vectors Derived from Adeno-Associated Virus (AAV) Serotypes Other Than AAV Type 2 , 1998, Journal of Virology.

[152]  S. Leff,et al.  Midbrain injection of recombinant adeno-associated virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamine-induced degeneration model of Parkinson's disease in rats. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[153]  D. Bohl,et al.  Efficient and stable adeno-associated virus-mediated transduction in the skeletal muscle of adult immunocompetent mice. , 1997, Human gene therapy.

[154]  S. Ponnazhagan,et al.  Encapsidation of adeno-associated virus type 2 Rep proteins in wild-type and recombinant progeny virions: Rep-mediated growth inhibition of primary human cells , 1997, Journal of virology.

[155]  A. Gown,et al.  Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors , 1997, Nature Genetics.

[156]  W. Hauswirth,et al.  Efficient photoreceptor-targeted gene expression in vivo by recombinant adeno-associated virus. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[157]  N. Muzyczka,et al.  The adeno-associated virus type 2 p40 promoter requires a proximal Sp1 interaction and a p19 CArG-like element to facilitate Rep transactivation , 1997, Journal of virology.

[158]  N. Muzyczka,et al.  The cellular transcription factor SP1 and an unknown cellular protein are required to mediate Rep protein activation of the adeno-associated virus p19 promoter , 1997, Journal of virology.

[159]  N. Muzyczka,et al.  The adeno-associated virus (AAV) Rep protein acts as both a repressor and an activator to regulate AAV transcription during a productive infection , 1997, Journal of virology.

[160]  B. Byrne,et al.  Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[161]  R. Samulski,et al.  Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector , 1996, Journal of virology.

[162]  T. Flotte,et al.  Safety of single-dose administration of an adeno-associated virus (AAV)-CFTR vector in the primate lung. , 1996, Gene therapy.

[163]  T. Flotte,et al.  A phase I study of an adeno-associated virus-CFTR gene vector in adult CF patients with mild lung disease. , 1996, Human gene therapy.

[164]  T. Samulski,et al.  Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors , 1996, Journal of virology.

[165]  T. Flotte,et al.  In vivo model of adeno-associated virus vector persistence and rescue , 1996, Journal of virology.

[166]  M. Weitzman,et al.  Interaction of wild-type and mutant adeno-associated virus (AAV) Rep proteins on AAV hairpin DNA , 1996, Journal of virology.

[167]  G. Breese,et al.  Differential and persistent expression patterns of CNS gene transfer by an adeno-associated virus (AAV) vector , 1996, Brain Research.

[168]  J. Ryan,et al.  Sequence requirements for binding of Rep68 to the adeno-associated virus terminal repeats , 1996, Journal of virology.

[169]  J. Trempe,et al.  The adeno-associated virus Rep78 protein is covalently linked to viral DNA in a preformed virion. , 1995, Virology.

[170]  Philip R. Johnson,et al.  Cell lines for the production of recombinant adeno-associated virus. , 1995, Human gene therapy.

[171]  F. Hoppe-Seyler,et al.  Mutational analysis of adeno-associated virus Rep protein-mediated inhibition of heterologous and homologous promoters , 1995, Journal of virology.

[172]  T. Flotte,et al.  Adeno-associated virus vector gene expression occurs in nondividing cells in the absence of vector DNA integration. , 1994, American journal of respiratory cell and molecular biology.

[173]  R. Kotin,et al.  Sequence requirements for stable binding and function of Rep68 on the adeno-associated virus type 2 inverted terminal repeats , 1994, Journal of virology.

[174]  J. Ryan,et al.  Identification of linear DNA sequences that specifically bind the adeno-associated virus Rep protein , 1994, Journal of virology.

[175]  M. Weitzman,et al.  Adeno-associated virus (AAV) Rep proteins mediate complex formation between AAV DNA and its integration site in human DNA. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[176]  R. Samulski,et al.  Features of the adeno-associated virus origin involved in substrate recognition by the viral Rep protein , 1993, Journal of virology.

[177]  M. Drumm,et al.  Expression of the cystic fibrosis transmembrane conductance regulator from a novel adeno-associated virus promoter. , 1993, The Journal of biological chemistry.

[178]  D. Klessig,et al.  Adenovirus containing a deletion of the early region 2A gene allows growth of adeno-associated virus with decreased efficiency. , 1992, Virology.

[179]  N. Muzyczka,et al.  Partial purification of adeno-associated virus Rep78, Rep52, and Rep40 and their biochemical characterization , 1992, Journal of virology.

[180]  D. Housman,et al.  Targeted integration of adeno‐associated virus (AAV) into human chromosome 19. , 1991, The EMBO journal.

[181]  Yang Shi,et al.  Transcriptional repression by YY1, a human GLI-Krüippel-related protein, and relief of repression by adenovirus E1A protein , 1991, Cell.

[182]  R. Heilbronn,et al.  A subset of herpes simplex virus replication genes provides helper functions for productive adeno-associated virus replication , 1991, Journal of virology.

[183]  N. Muzyczka,et al.  The AAV origin binding protein Rep68 is an ATP-dependent site-specific endonuclease with DNA helicase activity , 1990, Cell.

[184]  T. Shenk,et al.  The adenovirus DNA-binding protein stimulates the rate of transcription directed by adenovirus and adeno-associated virus promoters , 1990, Journal of virology.

[185]  Lynne,et al.  Site-specific integration by adeno-associated virus. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[186]  Samulski,et al.  Helper-free stocks of recombinant adeno-associated viruses: normal integration does not require viral gene expression , 1989, Journal of virology.

[187]  Y. Shi,et al.  Adeno-associated virus P5 promoter contains an adenovirus E1A-inducible element and a binding site for the major late transcription factor , 1989, Journal of virology.

[188]  P. Hearing,et al.  Adenovirus early region 4 encodes two gene products with redundant effects in lytic infection , 1989, Journal of virology.

[189]  P. Fabisch,et al.  Synthesis of adeno-associated virus structural proteins requires both alternative mRNA splicing and alternative initiations from a single transcript , 1988, Journal of virology.

[190]  P. Collis,et al.  Adeno-associated virus general transduction vectors: analysis of proviral structures , 1988, Journal of virology.

[191]  R. Samulski,et al.  Adenovirus E1B 55-Mr polypeptide facilitates timely cytoplasmic accumulation of adeno-associated virus mRNAs , 1988, Journal of virology.

[192]  R. Samulski,et al.  A recombinant plasmid from which an infectious adeno-associated virus genome can be excised in vitro and its use to study viral replication , 1987, Journal of virology.

[193]  J. Tratschin,et al.  A human parvovirus, adeno-associated virus, as a eucaryotic vector: transient expression and encapsidation of the procaryotic gene for chloramphenicol acetyltransferase , 1984, Molecular and cellular biology.

[194]  N. Muzyczka,et al.  Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[195]  J. Tratschin,et al.  Genetic analysis of adeno-associated virus: properties of deletion mutants constructed in vitro and evidence for an adeno-associated virus replication function , 1984, Journal of virology.

[196]  M. Labow,et al.  Genetics of adeno-associated virus: isolation and preliminary characterization of adeno-associated virus type 2 mutants , 1984, Journal of virology.

[197]  A. Srivastava,et al.  Nucleotide sequence and organization of the adeno-associated virus 2 genome , 1983, Journal of virology.

[198]  R. Spaete,et al.  The herpes simplex virus amplicon: A new eucaryotic defective-virus cloning-amplifying vector , 1982, Cell.

[199]  R. Samulski,et al.  Cloning of adeno-associated virus into pBR322: rescue of intact virus from the recombinant plasmid in human cells. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[200]  H. Temin,et al.  Formation of infectious progeny virus after insertion of herpes simplex thymidine kinase gene into DNA of an avian retrovirus , 1981, Cell.

[201]  J. Janik,et al.  Herpes Simplex Virus Types 1 and 2 Completely Help Adenovirus-Associated Virus Replication , 1981, Journal of virology.

[202]  E. Scolnick,et al.  Construction and isolation of a transmissible retrovirus containing the src gene of Harvey murine sarcoma virus and the thymidine kinase gene of herpes simplex virus type 1 , 1981, Journal of virology.

[203]  D. Solnick.  Construction of an adenovirus-SV40 recombinant producing SV40 T antigen from an adenovirus late promoter , 1981, Cell.

[204]  J. Janik,et al.  Locations of adenovirus genes required for the replication of adenovirus-associated virus. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[205]  B. Carter,et al.  Adeno-associated virus replication. The effect of L-canavanine or a helper virus mutation on accumulation of viral capsids and progeny single-stranded DNA. , 1981, The Journal of biological chemistry.

[206]  M. Nicholas.  Construction of an SV40-derived cloning vector , 1980 .

[207]  K. Berns,et al.  Nucleotide sequence of the inverted terminal repetition in adeno-associated virus DNA , 1980, Journal of virology.

[208]  S. Goff,et al.  Construction of hybrid viruses containing SV40 and λ phage DNA segments and their propagation in cultured monkey cells , 1976, Cell.

[209]  D. Ganem,et al.  Propagation of a segment of bacteriophage λ-DNA in monkey cells after covalent linkage to a defective simian virus 40 genome , 1976, Cell.

[210]  H. Ginsberg,et al.  DNA-Minus Temperature-Sensitive Mutants of Adenovirus Type 5 Help Adenovirus-Associated Virus Replication , 1976, Journal of virology.

[211]  B. Casto,et al.  Adenovirus-Associated Defective Virus Particles , 1965, Science.

[212]  J. F. Wright,et al.  Undetectable transcription of cap in a clinical AAV vector: implications for preformed capsid in immune responses. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[213]  M. Perrier,et al.  Critical assessment of current adeno-associated viral vector production and quantification methods. , 2008, Biotechnology advances.

[214]  T. Clackson,et al.  Rapamycin control of transgene expression from a single AAV vector in mouse salivary glands , 2006, Gene Therapy.

[215]  P. Reier,et al.  Efficient transduction of green fluorescent protein in spinal cord neurons using adeno-associated virus vectors containing cell type-specific promoters , 1997, Gene Therapy.

[216]  Donald W. Pfaff,et al.  Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain , 1994, Nature Genetics.

[217]  W. Hauswirth,et al.  Origin and termination of adeno-associated virus DNA replication. , 1977, Virology.

[218]  Y. Kan,et al.  Adeno-Associated Viral Vector Delivered Cardiac-Specific and Hypoxia-Inducible VEGF Expression in the Ischemic Mouse Hearts , 2022 .