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Gene Therapy with Helper-Dependent Adenoviral Vectors: Current Advances and Future Perspectives

By Francesco Vetrini and Philip Ng

Abstract

Recombinant Adenoviral vectors represent one of the best gene transfer platforms due to their ability to efficiently transduce a wide range of quiescent and proliferating cell types from various tissues and species. The activation of an adaptive immune response against the transduced cells is one of the major drawbacks of first generation Adenovirus vectors and has been overcome by the latest generation of recombinant Adenovirus, the Helper-Dependent Adenoviral (HDAd) vectors. HDAds have innovative features including the complete absence of viral coding sequences and the ability to mediate high level transgene expression with negligible chronic toxicity. This review summarizes the many aspects of HDAd biology and structure with a major focus on in vivo gene therapy application and with an emphasis on the unsolved issues that these vectors still presents toward clinical application

Topics: Review
Publisher: Molecular Diversity Preservation International (MDPI)
OAI identifier: oai:pubmedcentral.nih.gov:3186006
Provided by: PubMed Central

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Citations

  1. (2004). [Hydrodynamics-based transfer of human apolipoprotein A-I gene into mice: study of factors involving an efficacy and duration of the transferred gene expression in animals' liver].
  2. (2008). A critical role for type I IFN-dependent NK cell activation in innate immune elimination of adenoviral vectors in vivo.
  3. (1993). A far-downstream hepatocyte-specific control region directs expression of the linked human apolipoprotein E and C-I genes in transgenic mice.
  4. (1996). A helper-dependent adenovirus vector system: removal of helper virus by Cre-mediated excision of the viral packaging signal.
  5. (1997). A helper-dependent system for adenovirus vector production helps define a lower limit for efficient DNA
  6. (1993). A model system for in vivo gene transfer into the central nervous system using an adenoviral
  7. (1999). A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis. Hum. Gene Ther.
  8. (1994). Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver.
  9. (2008). Absence of an intrathecal immune reaction to a helper-dependent adenoviral vector delivered into the cerebrospinal fluid of nonhuman primates. Gene Ther.
  10. (2004). Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates. Hum. Gene Ther.
  11. (2005). Adeno-associated virus-vectored gene therapy for retinal disease. Hum. Gene Ther.
  12. (1999). Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in
  13. (2007). Adenoviral infection induces a multi-faceted innate cellular immune response that is mediated by the toll-like receptor pathway in A549 cells. Virology
  14. (2009). Adenovirus activates complement by distinctly different mechanisms in vitro and in vivo: indirect complement activation by virions in
  15. (2005). Adenovirus binding to blood factors results in liver cell infection and
  16. (2007). Adenovirus infection triggers a rapid, MyD88-regulated transcriptome response critical to acutephase and adaptive immune responses in
  17. (2008). Adenovirus serotype 5 hexon mediates liver gene transfer. Cell
  18. (1997). Adenovirus type 5 fiber knob binds to MHC class I alpha2 domain at the surface of human epithelial and B lymphoblastoid cells.
  19. (2002). Adenovirus vector-induced inflammation:
  20. (2008). Adenovirus vector-induced innate inflammatory mediators, MAPK signaling, as well as adaptive immune responses are dependent upon both TLR2 and TLR9
  21. (1999). Adenovirus vectors for gene delivery.
  22. (2009). Adenovirus virion stability and the viral genome: size matters.
  23. (2007). Adenovirus-induced thrombocytopenia: the role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance. Blood
  24. (2002). Adenovirus-mediated gene transfer to nonparenchymal cells in normal and injured liver.
  25. (1994). Adenovirus-mediated in vivo gene transfer into the central nervous system of a nonhuman primate (resident award paper).
  26. (1993). Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: biological efficacy study. Hum. Gene Ther.
  27. (1993). Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: toxicity study. Hum. Gene Ther.
  28. (2007). Adenovirus-platelet interaction in blood causes virus sequestration to the reticuloendothelial system of the liver.
  29. (1999). Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons.
  30. (2008). Advances in helper-dependent adenoviral vector research. Curr. Gene Ther.
  31. (2001). An improved helper-dependent adenoviral vector allows persistent gene expression after intramuscular delivery and overcomes preexisting immunity to adenovirus.
  32. (2000). and microtubule-mediated translocation of adenovirus serotype 5 occurs after endosomal lysis. Hum. Gene Ther.
  33. and TRIFinteracting TLRs differentially modulate several adenovirus vector-induced immune responses.
  34. (1994). ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum.
  35. (2008). Barriers for retinal gene therapy: separating fact from fiction. Vision Res.
  36. (2002). Bilamellar cationic liposomes protect adenovectors from preexisting humoral immune responses.
  37. (2010). by the authors; licensee MDPI,
  38. (2009). Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors.
  39. (2007). CD8(+) T-cell responses to adeno-associated virus capsid in humans.
  40. (2006). Cell type- and region-dependent coxsackie adenovirus receptor expression in the central nervous system.
  41. (1998). Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: implications for gene therapy.
  42. (1994). Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy.
  43. (2003). Characterization of in vitro and in vivo gene transfer properties of adenovirus serotype 35 vector.
  44. (2008). Characterization of pulmonary T cell response to helper-dependent adenoviral vectors following intranasal delivery.
  45. (2008). Clearance of adenovirus by Kupffer cells is mediated by scavenger receptors, natural antibodies, and
  46. (2005). Coates,A.L.; Hu,J. Aerosol delivery of an enhanced helper-dependent adenovirus formulation to rabbit lung using an intratracheal
  47. (2010). Common control of the heat shock gene and early adenovirus genes: evidence for a cellular E1A-like activity.
  48. (2009). Comparison of replication-competent, first generation, and helper-dependent adenoviral vaccines. PLoS. One
  49. (2001). Complement activation by recombinant adenoviruses. Gene Ther.
  50. (1983). Covalently closed circles of adenovirus 5 DNA. Nature
  51. (2010). Cystic fibrosis-related diabetes in childhood.
  52. (2001). Development of a FLP/frt system for generating helper-dependent adenoviral vectors.
  53. (1993). Direct gene transfer of human CFTR into human bronchial epithelia of xenografts with E1-deleted adenoviruses.
  54. (2008). Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science
  55. (2001). Dystrophin expression in muscle following gene transfer with a fully deleted ("gutted") adenovirus is markedly improved by trans-acting adenoviral gene products. Hum. Gene Ther.
  56. (1985). Edetate sodium aerosol in Pseudomonas lung infection in cystic fibrosis.
  57. (2009). Effect of tissue-specific promoters and microRNA recognition elements on stability of transgene expression after hydrodynamic naked plasmid DNA delivery. Hum. Gene Ther.
  58. (1999). Effects of stuffer DNA on transgene expression from helper-dependent adenovirus vectors.
  59. (1992). Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis.
  60. (2001). Efficient FLPe recombinase enables scalable production of helper-dependent adenoviral vectors with negligible helper-virus contamination.
  61. (2001). EGTA enhancement of adenovirus-mediated gene transfer to mouse tracheal epithelium in
  62. (2005). Elimination of innate immune responses and liver inflammation by PEGylation of adenoviral vectors
  63. (2003). Episomal persistence of recombinant adenoviral vector genomes during the cell cycle in
  64. (2005). Evaluation of polyethylene glycol modification of first-generation and helper-dependent adenoviral vectors to reduce innate immune responses.
  65. (2000). Evaluation of the biodistribution, persistence, toxicity, and potential of germ-line transmission of a replication-competent human adenovirus following intraprostatic administration in the mouse.
  66. (2000). Expression of the adenovirus receptor and its interaction with the fiber knob. Exp. Cell Res.
  67. (2006). Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature
  68. (2003). Fetal muscle gene transfer is not enhanced by an RGD capsid modification to high-capacity adenoviral vectors. Gene Ther.
  69. (1998). Fluorescent virions: dynamic tracking of the pathway of adenoviral gene transfer vectors in living cells. Hum. Gene Ther.
  70. (1995). Gene expression from recombinant viral vectors in the central nervous system after blood-brain barrier disruption. Neurosurgery
  71. (2010). Genetic counselling issues in cystic fibrosis.
  72. (1997). HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses.
  73. (2006). Helper-dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia A
  74. (2001). Helper-dependent adenoviral vector-mediated gene transfer in aged rat
  75. (2004). Helper-dependent adenoviral vectors containing modified fiber for improved transduction of developing and mature muscle cells. Hum. Gene Ther.
  76. (2005). Helper-dependent adenoviral vectors in experimental gene therapy.
  77. (2004). Helper-dependent adenoviral vectors mediate therapeutic factor VIII expression for several months with minimal accompanying toxicity in a canine model of severe hemophilia A. Blood
  78. (2004). Helper-dependent adenovirus vectors elicit intact innate but attenuated adaptive host immune responses in
  79. (2008). Helper-dependent adenovirusmediated short hairpin RNA expression in the liver activates the interferon response.
  80. (2002). Helperdependent adenoviral vectors efficiently express transgenes in human dendritic cells but still stimulate antiviral immune responses.
  81. (2007). Highcapacity adenoviral vector-mediated reduction of huntingtin aggregate load in vitro and in
  82. (1988). Hypoxemia during sleep in Duchenne muscular dystrophy.
  83. (2009). Identification of coagulation factor (F)X binding sites on the adenovirus serotype 5 hexon: effect of mutagenesis on FX interactions and gene transfer. Blood
  84. (2008). IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis. Gene Ther.
  85. (2008). Immunity to adeno-associated virus vectors in animals and humans: a continued challenge. Gene Ther.
  86. (1996). Immunological instability of persistent adenovirus vectors in the brain: peripheral exposure to vector leads to renewed inflammation, reduced gene expression, and demyelination.
  87. (2006). Improved hepatic transduction, reduced systemic vector dissemination, and long-term transgene expression by delivering helper-dependent adenoviral vectors into the surgically isolated liver of nonhuman primates. Hum. Gene Ther.
  88. (2003). Improved system for helper-dependent adenoviral vector production.
  89. (1998). In vitro and in vivo biology of recombinant adenovirus vectors with E1, E1/E2A, or E1/E4
  90. (1994). Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis.
  91. (2005). Increased hepatic transduction with reduced systemic dissemination and proinflammatory cytokines following hydrodynamic injection of helper-dependent adenoviral vectors.
  92. (2000). Increasing epithelial junction permeability enhances gene transfer to airway epithelia In
  93. (2008). Inducing huntingtin inclusion formation in primary neuronal cell culture and in vivo by high-capacity adenoviral vectors expressing truncated and full-length huntingtin with polyglutamine expansion.
  94. (2007). Influence of coagulation factor zymogens on the infectivity of adenoviruses pseudotyped with fibers from subgroup
  95. (2007). Innate immune response to adenoviral vectors is mediated by both Toll-like receptor-dependent and -independent
  96. (1993). Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell
  97. (2004). Intravenous administration of an AAV-2 vector for the expression of factor IX in mice and a dog model of hemophilia B. Gene Ther.
  98. (1996). Lack of persistence of E1- recombinant adenoviral vectors containing a temperature-sensitive E2A mutation in immunocompetent mice and hemophilia B dogs. Gene Ther.
  99. (2002). Lethal toxicity, severe endothelial injury, and a threshold effect with high doses of an adenoviral vector in baboons. Hum. Gene Ther.
  100. (2005). Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector.
  101. (2001). Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector.
  102. (1998). Limited entry of adenovirus vectors into well-differentiated airway epithelium is responsible for inefficient gene
  103. (2009). long-term hepatic gene transfer using clinically relevant HDAd doses by balloon occlusion catheter delivery in nonhuman primates.
  104. (2002). Long-term transgene expression in the RPE after gene transfer with a high-capacity adenoviral vector.
  105. (2006). Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with CriglerNajjar disease.
  106. (2006). Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system.
  107. (2006). Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes. Blood
  108. NeuroDbetacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice.
  109. (2002). PEGylation of E1-deleted adenovirus vectors allows significant gene expression on readministration to liver. Hum. Gene Ther.
  110. (2009). Persistence of high-capacity adenoviral vectors as replication-defective monomeric genomes in vitro and in murine liver. Hum. Gene Ther.
  111. (2007). Polyethylene glycol modification of adenovirus reduces platelet activation, endothelial cell activation, and
  112. Potential of helper-dependent adenoviral vectors in modulating airway innate immunity.
  113. (1998). Potentiation of gene transfer to the mouse lung by complexes of adenovirus vector and polycations improves therapeutic potential. Hum. Gene Ther.
  114. (1987). Practical problems in the respiratory care of patients with muscular dystrophy.
  115. (1998). Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 genes
  116. (2008). Progress and prospects: gene therapy for genetic diseases with helperdependent adenoviral vectors. Gene Ther.
  117. (2010). Progress and prospects: immune responses to viral vectors. Gene Ther.
  118. (2009). Progress towards liver and lung-directed gene therapy with helperdependent adenoviral vectors. Curr. Gene Ther.
  119. (1994). Prolonged transgene expression in cotton rat lung with recombinant adenoviruses defective
  120. (2009). Protection against Mucosal SHIV Challenge by Peptide and HelperDependent Adenovirus Vaccines. Viruses.
  121. (2003). Protection of Cftr knockout mice from acute lung infection by a helperdependent adenoviral vector expressing Cftr in airway epithelia.
  122. (2007). Pseudo-hydrodynamic delivery of helper-dependent adenoviral vectors into non-human primates for liver-directed gene therapy.
  123. (1999). Receptors mediating adenovirus attachment and internalization.
  124. (2010). Reduced inflammation and improved airway expression using helper-dependent adenoviral vectors with a K18 promoter.
  125. (2009). Redundant and synergistic mechanisms control the sequestration of blood-born adenovirus in the liver.
  126. (2004). Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebo-controlled trial. Chest
  127. (2000). Rescue of skeletal muscles of gamma-sarcoglycan-deficient mice with adenoassociated virus-mediated gene transfer.
  128. (2000). Retargeting the coxsackievirus and adenovirus receptor to the apical surface of polarized epithelial cells reveals the glycocalyx as a barrier to adenovirus-mediated gene
  129. (2008). Robust hepatic gene silencing for functional studies using helper-dependent adenovirus vectors. Hum. Gene Ther.
  130. (1998). Role of E4 in eliciting CD4 Tcell and B-cell responses to adenovirus vectors delivered to murine and nonhuman primate lungs.
  131. (1996). Role of T cells in inflammation caused by adenovirus vectors in the brain. Gene Ther.
  132. (2003). Selective depletion or blockade of Kupffer cells leads to enhanced and prolonged hepatic transgene expression using high-capacity adenoviral vectors.
  133. (2007). Sensing infection by adenovirus: Toll-like receptor-independent viral DNA recognition signals activation of the interferon regulatory factor 3 master
  134. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver.
  135. (2000). Several log increase in therapeutic transgene delivery by distinct adeno-associated viral serotype vectors.
  136. (2009). Species differences in hepatocyte-directed gene transfer: implications for clinical translation. Curr. Gene Ther.
  137. (2001). Stable integration of transgenes delivered by a retrotransposon-adenovirus hybrid vector. Hum. Gene Ther.
  138. (1993). Stepwise dismantling of adenovirus 2 during entry into cells. Cell
  139. (2010). Study of the Efficacy, Biodistribution, and Safety Profile of Therapeutic Gutless Adenovirus Vectors as a Prelude to a Phase I Clinical Trial for Glioblastoma.
  140. (2002). Sustained human factor VIII expression in hemophilia A mice following systemic delivery of a gutless adenoviral vector.
  141. (2004). Sustained improvement of muscle function one year after full-length dystrophin gene transfer into mdx mice by a gutted helper-dependent adenoviral vector. Hum. Gene Ther.
  142. (2004). Sustained muscle expression of dystrophin from a high-capacity adenoviral vector with systemic gene transfer of T cell costimulatory blockade.
  143. (2005). Sustained phenotypic correction of canine hemophilia B after systemic administration of helper-dependent adenoviral vector. Hum. Gene Ther.
  144. (2002). Systemic delivery of a high-capacity adenoviral vector expressing mouse CTLA4Ig improves skeletal muscle gene therapy.
  145. (2000). Targeting adenovirus. Gene Ther.
  146. (1995). Targeting of adenovirus penton base to new receptors through replacement of its RGD motif with other receptor-specific peptide motifs. Gene Ther.
  147. (2007). Targeting of adenovirus serotype 5 (Ad5) and 5/47 pseudotyped vectors in vivo: fundamental involvement of coagulation factors and redundancy of CAR binding by Ad5.
  148. The role of liver sinusoidal cells in hepatocyte-directed gene transfer.
  149. (2004). Therapeutic gene transfer to dystrophic diaphragm by an adenoviral vector deleted of all viral genes.
  150. (2007). Toll-like receptor 9 triggers an innate immune response to helper-dependent adenoviral vectors.
  151. (1998). Toxicological comparison of E2a-deleted and first-generation adenoviral vectors expressing alpha1-antitrypsin after systemic delivery. Hum. Gene Ther.
  152. (1995). Transfer of the CFTR gene to the lung of nonhuman primates with E1-deleted, E2a-defective recombinant adenoviruses: a preclinical toxicology study. Hum. Gene Ther.
  153. (2009). Transient pretreatment with glucocorticoid ablates innate toxicity of systemically delivered adenoviral vectors without reducing efficacy.
  154. (2007). Type I IFN signaling on both B and CD4 T cells is required for protective antibody response to adenovirus.
  155. (2004). Vaccination with helperdependent adenovirus enhances the generation of transgene-specific CTL. Gene Ther.
  156. (2002). Variables affecting in vivo performance of high-capacity adenovirus vectors.
  157. (2010). Vasoactive Intestinal Peptide Increases Hepatic Transduction and Reduces Innate Immune Response Following Administration of Helper-dependent Ad.
  158. (2009). Virus binding to a plasma membrane receptor triggers interleukin-1 alpha-mediated proinflammatory macrophage response in vivo. Immunity