Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 α1-antitrypsin (AAT) vector in AAT-deficient adults

A phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 (rAAV2) α 1- 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 × 1012 vector genomes (VG) to 6.9 × 1013 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 × 1012 VG or higher. Anti-AAV2 capsid antibodies were present and rose ...