title: Long-term robust myocardial transduction of the dog heart from a peripheral vein by adeno-associated virus serotype-8.
abstract: Molecular intervention using noninvasive myocardial gene transfer holds great promise for treating heart diseases. Robust cardiac transduction from peripheral vein injection has been achieved in rodents using adeno-associated virus (AAV) serotype-9 (AAV-9). However, a similar approach has failed to transduce the heart in dogs, a commonly used large animal model for heart diseases. To develop an effective noninvasive method to deliver exogenous genes to the dog heart, we employed an AAV-8 vector that expresses human placental alkaline phosphatase reporter gene under the transcriptional regulation of the Rous sarcoma virus promoter. Vectors were delivered to three neonatal dogs at the doses of 1.35×10(14), 7.14×10(14), and 9.06×10(14) viral genome particles/kg body weight via the jugular vein. Transduction efficiency and overall safety were evaluated at 1.5, 2.5, and 12 months postinjection. AAV delivery was well tolerated and dog growth was normal. Blood chemistry and internal organ histology were unremarkable. Widespread skeletal muscle transduction was observed in all dogs without T-cell infiltration. Encouragingly, whole heart myocardial transduction was achieved in two dogs that received higher doses and cardiac expression lasted for at least 1 year. In summary, peripheral vein AAV-8 injection may represent a simple heart gene transfer method in large mammals. Further optimization of this gene delivery strategy may open the door for a readily applicable gene therapy method to treat many heart diseases.
authors.affiliation: Department of Molecular Microbiology and Immunology, The University of Missouri, Columbia, MO 65212, USA.
authors.forename: Xiufang
authors.initials: X
authors.lastname: Pan
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yue
authors.forename: Keqing
authors.initials: K
authors.lastname: Zhang
authors.forename: William
authors.initials: W
authors.lastname: Lostal
authors.forename: Jin-Hong
authors.initials: JH
authors.lastname: Shin
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Duan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000229:Dependovirus / Q000145:classification* / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D005260:Female; D016679:Genome, Viral / Q000235:genetics; D006801:Humans; D007275:Injections, Intravenous; D007601:Jugular Veins / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D012703:Serotyping; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods*
references.citation: Eur J Cardiothorac Surg. 2012 Apr;41(4):734-44; discussion 744-5
references.pmid: 22378855
references.citation: Gene Ther. 2007 Nov;14(22):1605-9
references.pmid: 17898796
references.citation: Hum Gene Ther. 2006 Apr;17(4):427-39
references.pmid: 16610930
references.citation: Mol Ther. 2008 Dec;16(12):1944-52
references.pmid: 18827804
references.citation: Mol Ther. 2006 Jul;14(1):45-53
references.pmid: 16713360
references.citation: J Card Fail. 2009 Apr;15(3):171-81
references.pmid: 19327618
references.citation: Circulation. 2011 Jul 19;124(3):304-13
references.pmid: 21709064
references.citation: Gene Ther. 2012 Jun;19(6):694-700
references.pmid: 22402323
references.citation: Methods Mol Biol. 2011;709:313-29
references.pmid: 21194038
references.citation: Mol Ther. 2009 Mar;17(3):409-16
references.pmid: 19107117
references.citation: Nat Biotechnol. 1999 Mar;17(3):241-5
references.pmid: 10096290
references.citation: Circ Res. 2006 Aug 18;99(4):e3-9
references.pmid: 16873720
references.citation: Lab Invest. 2011 Feb;91(2):216-31
references.pmid: 20714321
references.citation: Hum Gene Ther. 2012 Feb;23(2):202-9
references.pmid: 21967249
references.citation: Neuromuscul Disord. 2011 Jul;21(7):453-61
references.pmid: 21570848
references.citation: J Virol. 2012 Jun;86(12):6620-31
references.pmid: 22496229
references.citation: J Gene Med. 2011 Oct;13(10):573-86
references.pmid: 21954055
references.citation: Nat Rev Genet. 2009 Aug;10(8):578-85
references.pmid: 19609263
references.citation: Mol Ther. 2008 Apr;16(4):665-72
references.pmid: 18362924
references.citation: Hum Gene Ther. 2012 Jul;23(7):722-32
references.pmid: 22482463
references.citation: Res Rep Biol. 2011 Mar;2011(2):31-42
references.pmid: 21691429
references.citation: Nat Biotechnol. 2005 Mar;23(3):321-8
references.pmid: 15735640
references.citation: J Gene Med. 2011 Oct;13(10):556
references.pmid: 22025443
references.citation: Methods Mol Biol. 2012;798:267-84
references.pmid: 22130842
references.citation: Mol Ther. 2008 Dec;16(12):1953-1959
references.pmid: 28189009
references.citation: J Gene Med. 2011 Oct;13(10):566-72
references.pmid: 21954037
references.citation: Nat Med. 2004 Aug;10(8):828-34
references.pmid: 15273747
references.citation: J Gene Med. 2011 Oct;13(10):557-65
references.pmid: 21837689
references.citation: Hum Gene Ther. 2012 Mar;23(3):287-94
references.pmid: 22040468
references.citation: Mol Ther. 2008 Jun;16(6):1073-80
references.pmid: 18414476
references.citation: Gene Ther. 2012 Jun;19(6):678-85
references.pmid: 22318092
references.citation: Mol Ther. 2012 Jan;20(1):73-83
references.pmid: 21915102
references.citation: Curr Heart Fail Rep. 2012 Mar;9(1):33-9
references.pmid: 22143928