Adenovirus vector toxicity

Abstract

Adenovirus (Ad) vectors are one of the most commonly used classes of vectors being used in gene therapy clinical trials. However, vector-induced toxicity remains a significant barrier to safe, high-dose systemic therapy with Ad vectors. This review will describe what is known about the mechanisms of Ad-induced toxicity after administration of vector by the intravenous route, as well as how these toxicities can be mitigated. Given the hepatotropic nature of many commonly used Ad serotypes, the liver is a key site of virus-induced toxicity. Both innate and adaptive immunity contribute to hepatotoxicity. Intravenous delivery of Ad can also induce other rapid innate toxicities, including thrombocytopenia, systemic inflammation, fever and shock. Recent progress in understanding Ad biology has enabled improvements in vector safety and gene delivery efficiency in animal models, including genetic and chemical modification of the Ad vector itself, new ways to administer vector and pre-treatment with drugs that suppress innate and adaptive immune responses.