title: Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults.
abstract: A phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 (rAAV2) alpha1-antitrypsin (AAT) vector was performed in 12 AAT-deficient adults, 10 of whom were male. All subjects were either homozygous for the most common AAT mutation (a missense mutation designated PI*Z) or compound heterozygous for PI*Z and another mutation known to cause disease. There were four dose cohorts, ranging from 2.1 x 10(12) vector genomes (VG) to 6.9 x 10(13) VG, with three subjects per cohort. Subjects were injected sequentially in a dose-escalating fashion with a minimum of 14 days between patients. Subjects who had been receiving AAT protein replacement discontinued that therapy 28 days before vector administration. There were no vector-related serious adverse events in any of the 12 participants. Vector DNA sequences were detected in the blood between 1 and 3 days after injection in nearly all patients receiving doses of 6.9 x 10(12) VG or higher. Anti-AAV2 capsid antibodies were present and rose after vector injection, but no other immune responses were detected. One subject who had not been receiving protein replacement exhibited low-level expression of wild-type M-AAT in the serum (82 nM), which was detectable 30 days after receiving an injection of 2.1 x 10(13) VG. Unfortunately, residual but declining M-AAT levels from the washout of the protein replacement elevated background levels sufficiently to obscure any possible vector expression in that range in most of the other individuals in the higher dose cohorts.
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
authors.forename: L Terry
authors.initials: LT
authors.lastname: Spencer
authors.forename: Margaret
authors.initials: M
authors.lastname: Humphries
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Conlon
authors.forename: Carolyn T
authors.initials: CT
authors.lastname: Spencer
authors.forename: Amy
authors.initials: A
authors.lastname: Poirier
authors.forename: Wendy
authors.initials: W
authors.lastname: Garlington
authors.forename: Dawn
authors.initials: D
authors.lastname: Baker
authors.forename: Sihong
authors.initials: S
authors.lastname: Song
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Berns
authors.forename: Nicholas
authors.initials: N
authors.lastname: Muzyczka
authors.forename: Richard O
authors.initials: RO
authors.lastname: Snyder
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
mesh_terms: D000328:Adult; D000368:Aged; D004274:DNA, Recombinant / Q000097:blood; D000229:Dependovirus / Q000145:classification / Q000235:genetics* / Q000276:immunology; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007273:Injections, Intramuscular; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics / Q000276:immunology / Q000628:therapy*
chemical_list: D004274:DNA, Recombinant; D000515:alpha 1-Antitrypsin