title: Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy.
abstract: Alpha-1 antitrypsin (AAT) deficiency is well-suited as a target for human gene transfer. We performed a phase 1, open-label, dose-escalation clinical trial of a recombinant adeno-associated virus (rAAV) vector expressing normal (M) AAT packaged into serotype 1 AAV capsids delivered by i.m. injection. Nine AAT-deficient subjects were enrolled sequentially in cohorts of 3 each at doses of 6.9 x 10(12), 2.2 x 10(13), and 6.0 x 10(13) vector genome particles per patient. Four subjects receiving AAT protein augmentation discontinued therapy 28 or 56 days before vector administration. Vector administration was well tolerated, with only mild local reactions and 1 unrelated serious adverse event (bacterial epididymitis). There were no changes in hematology or clinical chemistry parameters. M-specific AAT was expressed above background in all subjects in cohorts 2 and 3 and was sustained at levels 0.1% of normal for at least 1 year in the highest dosage level cohort, despite development of neutralizing antibody and IFN-gamma enzyme-linked immunospot responses to AAV1 capsid at day 14 in all subjects. These findings suggest that immune responses to AAV capsid that develop after i.m. injection of a serotype 1 rAAV vector expressing AAT do not completely eliminate transduced cells in this context.
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Chulay
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Christian
authors.initials: C
authors.lastname: Mueller
authors.forename: Margaret
authors.initials: M
authors.lastname: Humphries
authors.forename: L Terry
authors.initials: LT
authors.lastname: Spencer
authors.forename: Farshid
authors.initials: F
authors.lastname: Rouhani
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Conlon
authors.forename: Roberto
authors.initials: R
authors.lastname: Calcedo
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: Carolyn
authors.initials: C
authors.lastname: Spencer
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
mesh_terms: D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002213:Capsid / Q000201:enzymology / Q000276:immunology; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics / Q000628:therapy*
chemical_list: D000914:Antibodies, Viral; D011993:Recombinant Fusion Proteins; D000515:alpha 1-Antitrypsin
references.citation: J Virol. 1999 Oct;73(10):8549-58
references.pmid: 10482608
references.citation: Am Rev Respir Dis. 1988 Feb;137(2):364-70
references.pmid: 3257660
references.citation: Hum Gene Ther. 2006 Jun;17(6):625-34
references.pmid: 16776571
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11854-9
references.pmid: 12192090
references.citation: Mol Ther. 2002 Sep;6(3):329-35
references.pmid: 12231168
references.citation: Curr Opin Biotechnol. 2002 Oct;13(5):418-23
references.pmid: 12459331
references.citation: Expert Opin Biol Ther. 2008 Apr;8(4):515-26
references.pmid: 18352854
references.citation: Chest. 1991 Sep;100(3):703-8
references.pmid: 1889260
references.citation: Hum Gene Ther. 1998 Dec 10;9(18):2745-60
references.pmid: 9874273
references.citation: J Infect Dis. 2009 Feb 1;199(3):381-90
references.pmid: 19133809
references.citation: Proc Natl Acad Sci U S A. 2003 May 13;100(10):6081-6
references.pmid: 12716974
references.citation: Trends Genet. 1989 Dec;5(12):411-7
references.pmid: 2696185
references.citation: Am J Med. 1988 Jun 24;84(6A):43-7
references.pmid: 3260072
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14082-7
references.pmid: 8943064
references.citation: Hum Gene Ther. 2008 Jul;19(7):663-9
references.pmid: 18549307
references.citation: AIDS Res Hum Retroviruses. 2007 Jan;23(1):67-76
references.pmid: 17263635
references.citation: Gene Ther. 1996 Mar;3(3):201-11
references.pmid: 8646550
references.citation: Clin Pharmacokinet. 1992 Aug;23(2):161-8
references.pmid: 1511530
references.citation: J Clin Invest. 1991 Mar;87(3):1060-5
references.pmid: 1999486
references.citation: Hum Gene Ther. 1997 Apr 10;8(6):659-69
references.pmid: 9113506
references.citation: Methods. 2002 Oct;28(2):158-67
references.pmid: 12413414
references.citation: Blood. 2006 Jun 15;107(12):4781-9
references.pmid: 16467198
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14384-8
references.pmid: 9826709
references.citation: Chest. 1989 Jan;95(1):196-208
references.pmid: 2642408
references.citation: Hum Gene Ther. 2007 Mar;18(3):245-56
references.pmid: 17376008
references.citation: Hum Gene Ther. 2006 Dec;17(12):1177-86
references.pmid: 17115945
references.citation: Mol Ther. 2001 Sep;4(3):217-22
references.pmid: 11545612
references.citation: Nat Med. 2006 Mar;12(3):342-7
references.pmid: 16474400
references.citation: Ann Pharmacother. 2008 May;42(5):640-6
references.pmid: 18413692