Deficiency of alpha-1 antitrypsin (AAT) is a relatively common genetic disorder, which leads to emphysema in the majority of symptomatic patients. While AAT is normally produced in the liver, and to a lesser extent in monocytes and macrophages, our laboratory has developed a clinical rAAV1-hAAT vector which mediates long-term, ectopic supplementation from muscle, thus avoiding potential for liver toxicity, which may be more likely in the AAT-deficient liver. The current vector has progressed through IM phase 1 and phase 2a trials which have shown dose-related expression persisting for years after 1 IM injection and the presence of regulatory T cells (Tregs) specific for AAV capsid. In the current application, we propose to complete preclinical studies necessary to move to the phase 2b trial, to complete that trial and to develop a method to study and control the Treg response, using novel humanized mouse models. The project is highly interactive with each of the cores and with projects 2, 3 and 4.
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