Safety of Intravenous Administration of an AAV8 Vector Coding for an Oxidation Resistant Human α1-antitrypsin for the Treatment of α1-antitrypsin Deficiency.
Academic Article
Overview
abstract
α1-antitrypsin (AAT) deficiency is a common autosomal recessive hereditary disorder, with a high risk for the development of early onset panacinar emphysema. AAT produced primarily in the liver, functions to protect the lung from neutrophil protease; with AAT deficiency, unimpeded neutrophil proteases destroy the lung parenchyma. AAT is susceptible to oxidative damage resulting in an inability to inhibit its target proteases, neutrophil elastase and cathepsin G. The major sites of oxidative modification on the AAT molecule are methionine residues 351 and 358. We have previously demonstrated that an engineered variant of AAT that resists oxidation by modifying both protein surface methionines ( M351V, M358L) provides antiprotease protection despite oxidative stress. In mice, intravenous delivery of the modified AAT(AVL) variant via AAV serotype 8, AAV8hAAT(AVL), primarily to the liver resulted in long-term expression of an AAT that resists oxidative inactivation. In this study we evaluated the safety of intravenous administration of AAV8hAAT(AVL) in a dose escalating, blinded, placebo-controlled toxicology study in wildtype mice. The study assessed organ histology and clinical pathology findings of mice, intravenously administered AAV8hAAT(AVL) at 3 doses (5.0x1011, 5.0x1012 and 5.0x1013 gc/kg) compared to control mice injected intravenously with PBS. As previously demonstrated, administration of AAV8hAAT(AVL) resulted in dose-dependent expression of high, potentially therapeutic, levels of serum human AT protein that persist for at least 6 months. Antibodies against the AAV8 capsid were elicited as expected, but there were no antibodies detected against the AAT(AVL) protein generated by the AAV8hAAT(AVL) vector. There was no morbidity or mortality observed in the study. The data demonstrates that intravenous administration of AAV8hAAT(AVL) is safe with no significant adverse effects attributed to AAV8hAAT(AVL) vector at any dose. This study demonstrates that AAV8hAAT(AVL) has a safety profile consistent with the requirements for proceeding to a clinical study.
