title: Efficient transduction of vascular smooth muscle cells with a translational AAV2.5 vector: a new perspective for in-stent restenosis gene therapy.
abstract: Coronary artery disease represents the leading cause of mortality in the developed world. Percutaneous coronary intervention involving stent placement remains disadvantaged by restenosis or thrombosis. Vascular gene therapy-based methods may be approached, but lack a vascular gene delivery vector. We report a safe and efficient long-term transduction of rat carotid vessels after balloon injury intervention with a translational optimized AAV2.5 vector. Compared with other known adeno-associated virus (AAV) serotypes, AAV2.5 demonstrated the highest transduction efficiency of human coronary artery vascular smooth muscle cells (VSMCs) in vitro. Local delivery of AAV2.5-driven transgenes in injured carotid arteries resulted in transduction as soon as day 2 after surgery and persisted for at least 30 days. In contrast to adenovirus 5 vector, inflammation was not detected in AAV2.5-transduced vessels. The functional effects of AAV2.5-mediated gene transfer on neointimal thickening were assessed using the sarco/endoplasmic reticulum Ca(2+) ATPase isoform 2a (SERCA2a) human gene, known to inhibit VSMC proliferation. At 30 days, human SERCA2a messenger RNA was detected in transduced arteries. Morphometric analysis revealed a significant decrease in neointimal hyperplasia in AAV2.5-SERCA2a-transduced arteries: 28.36±11.30 (n=8) vs 77.96±24.60 (n=10) μm(2), in AAV2.5-green fluorescent protein-infected, P<0.05. In conclusion, AAV2.5 vector can be considered as a promising safe and effective vector for vascular gene therapy.
authors.affiliation: INSERM, UMRS 956, Paris, France.
authors.forename: A-M
authors.initials: AM
authors.lastname: Lompré
authors.forename: L
authors.initials: L
authors.lastname: Hadri
authors.forename: E
authors.initials: E
authors.lastname: Merlet
authors.forename: Z
authors.initials: Z
authors.lastname: Keuylian
authors.forename: N
authors.initials: N
authors.lastname: Mougenot
authors.forename: I
authors.initials: I
authors.lastname: Karakikes
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: F
authors.initials: F
authors.lastname: Atassi
authors.forename: A
authors.initials: A
authors.lastname: Marchand
authors.forename: R
authors.initials: R
authors.lastname: Blaise
authors.forename: I
authors.initials: I
authors.lastname: Limon
authors.forename: S W J
authors.initials: SW
authors.lastname: McPhee
authors.forename: R J
authors.initials: RJ
authors.lastname: Samulski
authors.forename: R J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: L
authors.initials: L
authors.lastname: Lipskaia
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002339:Carotid Arteries / Q000166:cytology; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000628:therapy*; D003331:Coronary Vessels / Q000166:cytology; D000229:Dependovirus / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D058426:Neointima / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D000199:Actins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506948:Atp2a2 protein, rat; C498862:Acta2 protein, rat
references.citation: Circ Res. 2005 Sep 2;97(5):488-95
references.pmid: 16081870
references.citation: Circulation. 2000 Apr 25;101(16):1982-9
references.pmid: 10779466
references.citation: Circulation. 2003 Jun 3;107(21):2677-83
references.pmid: 12742981
references.citation: Virus Res. 2008 Mar;132(1-2):1-14
references.pmid: 18036698
references.citation: Expert Opin Biol Ther. 2007 Jun;7(6):809-21
references.pmid: 17555367
references.citation: Mol Ther. 2004 Feb;9(2):198-208
references.pmid: 14759804
references.citation: Mol Ther. 2006 Sep;14(3):316-27
references.pmid: 16824801
references.citation: J Gene Med. 2004 May;6(5):545-54
references.pmid: 15133765
references.citation: Coron Artery Dis. 1995 Jan;6(1):71-81
references.pmid: 7767506
references.citation: Gene Ther. 2008 Dec;15(23):1550-7
references.pmid: 18650850
references.citation: Mol Ther. 2010 Jul;18(7):1284-92
references.pmid: 20461063
references.citation: Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H760-7
references.pmid: 12124225
references.citation: Blood. 2010 Oct 14;116(15):2656-64
references.pmid: 20610817
references.citation: Circ J. 2011;75(6):1287-96
references.pmid: 21532177
references.citation: FASEB J. 2003 Jun;17(9):1183-5
references.pmid: 12709402
references.citation: Int J Cardiol. 2003 Aug;90(2-3):229-38
references.pmid: 12957756
references.citation: J Biol Chem. 2012 Jul 20;287(30):24978-89
references.pmid: 22613711
references.citation: Circ Res. 1998 Jun 29;82(12):1349-51
references.pmid: 9648732
references.citation: J Virol. 2000 Apr;74(8):3852-8
references.pmid: 10729159
references.citation: Pharmacol Ther. 2012 Oct;136(1):23-34
references.pmid: 22796519
references.citation: J Am Coll Cardiol. 2008 Mar 18;51(11):1112-9
references.pmid: 18342232
references.citation: Immunity. 2009 Jul 17;31(1):110-21
references.pmid: 19576795
references.citation: Proc Natl Acad Sci U S A. 1994 May 10;91(10):4407-11
references.pmid: 8183921
references.citation: Circ Res. 1993 Dec;73(6):1202-7
references.pmid: 8222091
references.citation: Br J Pharmacol. 2007 Sep;152(2):175-88
references.pmid: 17558439
references.citation: Circulation. 1999 Dec 7;100(23):2308-11
references.pmid: 10587333
references.citation: J Biol Chem. 2010 Jan 29;285(5):3510-23
references.pmid: 19933579
references.citation: Circ Res. 2003 May 30;92(10):1115-22
references.pmid: 12730091
references.citation: Hum Gene Ther. 2005 Feb;16(2):235-47
references.pmid: 15761263
references.citation: Physiol Genomics. 2000 Apr 27;2(3):117-27
references.pmid: 11015590
references.citation: Circulation. 2010 Feb 23;121(7):948-54
references.pmid: 20177011
references.citation: J Investig Med. 1997 Feb;45(2):87-98
references.pmid: 9084579
references.citation: N Engl J Med. 2010 Oct 7;363(15):1429-37
references.pmid: 20925545
references.citation: J Virol. 1998 Feb;72(2):1438-45
references.pmid: 9445046
references.citation: Cardiovasc Res. 1997 Sep;35(3):514-21
references.pmid: 9415296
references.citation: Circ Res. 1995 Sep;77(3):475-85
references.pmid: 7641320
references.citation: Circulation. 2008 Apr 22;117(16):2096-103
references.pmid: 18413497
references.citation: Mol Ther. 2011 Aug;19(8):1407-15
references.pmid: 21629221
references.citation: Mol Ther. 2012 Feb;20(2):443-55
references.pmid: 22068425
references.citation: J Card Fail. 2009 Apr;15(3):171-81
references.pmid: 19327618
references.citation: J Virol. 2010 Sep;84(17):8888-902
references.pmid: 20573820
references.citation: J Mol Cell Cardiol. 2011 Apr;50(4):621-33
references.pmid: 21195084
references.citation: Circulation. 1993 Dec;88(6):2838-48
references.pmid: 8252697
references.citation: Hum Gene Ther. 2000 Jan 20;11(2):263-70
references.pmid: 10680840
references.citation: Circ J. 2010 Sep;74(9):1830-6
references.pmid: 20622474
references.citation: J Am Coll Cardiol. 2002 Jan 16;39(2):281-7
references.pmid: 11788220
references.citation: Circ Res. 1998 Jun 29;82(12):1243-52
references.pmid: 9648720
references.citation: Gene Ther. 2013 Mar;20(3):248-54
references.pmid: 22456325
references.citation: J Gene Med. 2008 Feb;10(2):143-51
references.pmid: 18067196
references.citation: Curr Atheroscler Rep. 2003 May;5(3):186-90
references.pmid: 12667430
references.citation: Cardiovasc Revasc Med. 2007 Oct-Dec;8(4):230-5
references.pmid: 18053943
references.citation: Circulation. 2011 Jul 19;124(3):304-13
references.pmid: 21709064
references.citation: Gene Ther. 2002 Nov;9(22):1487-91
references.pmid: 12407420
references.citation: Mol Ther. 2001 Sep;4(3):174-81
references.pmid: 11545607
references.citation: J Card Fail. 2008 Jun;14(5):355-67
references.pmid: 18514926
references.citation: Biochem J. 1990 Nov 1;271(3):649-53
references.pmid: 2244871
references.citation: Mol Ther. 2003 May;7(5 Pt 1):597-603
references.pmid: 12718902
references.citation: Gene Ther. 2013 Apr;20(4):396-406
references.pmid: 22763406
references.citation: Circulation. 2004 Feb 3;109(4):513-9
references.pmid: 14732747
references.citation: Gene Ther. 1997 Aug;4(8):757-61
references.pmid: 9338002