title: Transgene expression up to 7 years in nonhuman primates following hepatic transduction with helper-dependent adenoviral vectors.
abstract: Helper-dependent adenoviral vectors (HDAd) have been shown to mediate a considerably longer duration of transgene expression than first-generation adenoviral vectors. We have previously shown that transgene expression from HDAd-transduced hepatocytes can persist at high levels for up to 2.6 years in nonhuman primates following a single-vector administration. Because duration of transgene expression and long-term toxicity are critical for risk:benefit assessment, we have continued to monitor these animals. We report here that transgene expression has persisted for the entire observation period of up to 7 years for all animals without long-term adverse effects. However, in all cases, transgene expression level slowly declined over time to less than 10% of peak values by the end of the observation period but remained 2.3-111-fold above baseline values. These results will provide important information for a more informed risk:benefit assessment before clinical application of HDAd.
authors.affiliation: Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Brunetti-Pierri
authors.forename: Thomas
authors.initials: T
authors.lastname: Ng
authors.forename: David
authors.initials: D
authors.lastname: Iannitti
authors.forename: William
authors.initials: W
authors.lastname: Cioffi
authors.forename: Gary
authors.initials: G
authors.lastname: Stapleton
authors.forename: Mark
authors.initials: M
authors.lastname: Law
authors.forename: John
authors.initials: J
authors.lastname: Breinholt
authors.forename: Donna
authors.initials: D
authors.lastname: Palmer
authors.forename: Nathan
authors.initials: N
authors.lastname: Grove
authors.forename: Karen
authors.initials: K
authors.lastname: Rice
authors.forename: Cassondra
authors.initials: C
authors.lastname: Bauer
authors.forename: Milton
authors.initials: M
authors.lastname: Finegold
authors.forename: Arthur
authors.initials: A
authors.lastname: Beaudet
authors.forename: Charles
authors.initials: C
authors.lastname: Mullins
authors.forename: Philip
authors.initials: P
authors.lastname: Ng
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics*; D006378:Helper Viruses / Q000235:genetics*; D008099:Liver / Q000187:drug effects*; D010215:Papio; D013995:Time; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics*
references.citation: Mol Ther. 2012 Oct;20(10):1863-70
references.pmid: 22828499
references.citation: Mol Ther. 2003 Nov;8(5):846-52
references.pmid: 14599819
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13282-7
references.pmid: 11687662
references.citation: Mol Ther. 2009 Feb;17(2):327-33
references.pmid: 19050700
references.citation: Mech Ageing Dev. 2002 Sep;123(11):1461-7
references.pmid: 12425953
references.citation: J Thromb Haemost. 2006 Jun;4(6):1218-1225
references.pmid: 16706963
references.citation: J Virol. 2001 May;75(10):4792-801
references.pmid: 11312351
references.citation: Mol Ther. 2005 Dec;12(6):1043-51
references.pmid: 16139571
references.citation: Hum Gene Ther. 2005 Jul;16(7):811-20
references.pmid: 16000063
references.citation: Mol Ther. 2005 Jul;12(1):99-106
references.pmid: 15963925
references.citation: Mol Ther. 2007 Apr;15(4):732-40
references.pmid: 17285138
references.citation: Hum Gene Ther. 2006 Apr;17(4):391-404
references.pmid: 16610927
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):3930-5
references.pmid: 15753292
references.citation: Mol Ther. 2004 Oct;10(4):792-8
references.pmid: 15451463