Characterization of adenovirus serotype 35 vectors using genetically modified animals and non-human primates

摘要

Recombinant Adenovirus (Ad) vectors are considered to be a promising gene delivery vehicle of high utility because they are easy to construct, can be produced at high titers, and efficiently transduce various types of cells. Ad vectors commonly used in the world, including clinical trials, are composed of Ad serotype 5 (Ad5), which belongs to subgroup C. In recent years, however, it has become apparent that Ad5 vectors have some drawbacks, such as high seroprevalence of anti-Ad5 antibodies in adults and low transduction efficiencies of Ad5 vectors in cells lacking a primary receptor for Ad5, coxsackievirus and adenovirus receptor (CAR). To overcome these limitations of Ad5 vectors, we have developed a novel type of Ad vector, which is composed of Ad serotype 35 (Ad35), belonging to subgroup B. Ad35 vectors recognize human CD46, not CAR, as a cellular receptor for infection. Human CD46 is expressed in almost all of human cells, leading to a broad tropism of Ad35 vectors to human cells, in contrast, expression of rodent CD46 is limited to the testis. Therefore, in vivo transduction properties of Ad35 vectors are not appropriately evaluated in normal mice. In order to evaluate the in vivo transduction properties of Ad35 vectors, Ad35 vectors were applied to human CD46-transgenic mice and nonhuman primates, which express CD46 in a similar pattern to humans. The data obtained using CD46-transgenic mice and nonhuman primates would provide valuable information towards clinical applications of Ad35 vectors.