Adenovirus serotype 35 vector-mediated transduction following direct administration into organs of nonhuman primates

Abstract

Adenovirus (Ad) serotype 35 (Ad35) vectors have attracted remarkable attention as alternatives to conventional Ad serotype 5 (Ad5) vectors. In a previous study, we showed that intravenously administered Ad35 vectors exhibited a safer profile than Ad5 vectors in cynomolgus monkeys, which ubiquitously express CD46, an Ad35 receptor, in a pattern similar to that in humans. However, the Ad35 vectors poorly transduced the organs. In this study, we examined the transduction properties of Ad35 vectors after local administration into organs of cynomolgus monkeys. The vectors transduced different types of cells depending on the organ. Hepatocytes and microglia were mainly transduced after the vectors were injected into the liver and cerebrum, respectively. Injection of the vectors into the femoral muscle resulted in the transduction of cells that appeared to be fibroblasts and/or macrophages. Conjunctival epithelial cells showed transgene expression following infusion into the vitreous body of the eyeball. Transgene expression was limited to areas around the injection points in most of the organs. In contrast, Ad35 vector-mediated transgene expression was not detected in any of the organs not injected with Ad35 vectors. These results suggest that Ad35 vectors are suitable for gene delivery by direct administration to organs.

Macropinocytotic Uptake and Infection of Human Epithelial Cells with Species B2 Adenovirus Type 35

“…For example, an Ad35-based malaria vaccine was shown to protect mice from Plasmodium falciparum sporozoites (77) and induced potent T-cell immunity (83). In addition, Ad35 vectors injected into tissues of nonhuman primates gave rise to specific gene expression at sites of injection in most organs, indicating the high versatility of Ad35 (86,87).…”

Gene doping detection: evaluation of approach for direct detection of gene transfer using erythropoietin as a model system

“…As summarized in Table 5, following intramuscular or intravenous delivery, rAAV or recombinant adenoviral vector was detected in serum or blood within several days and in peripheral blood mononuclear cells up to 10 months at levels significantly exceeding the minimal amounts detectable by the assays developed in our study. [15][16][17][18][19] Comparing performance parameters of assays 1, 2 and 3 with data from gene therapy clinical trials and animal studies for which details of a method for vectors detection and results on vector persistence are available ( Table 5), we concluded that direct detection of gene doping through gene transfer using the approach developed and tested in this project is feasible. As evidenced from the referenced papers, viral and nonviral vectors could be detected in blood components days, weeks and sometimes even months after vector transfer using PCR methods whose sensitivity was similar or lower (between several or hundred(s) times) than that of assays 1, 2 and 3.…”

Circumventing Antivector Immunity: Potential Use of Nonhuman Adenoviral Vectors

“…This indicates that these serotypes could be potentially used to evade preexisting immunity. Vectors have been developed from multiple HAdV serotypes with lower seroprevalence than HAdV-5: HAdV-11 (Holterman et al, 2004;Stone et al, 2005;Abbink et al, 2007), HAdV-35 (Gao et al, 2003;Sakurai et al, 2003Sakurai et al, , 2009Seshidhar Reddy et al, 2003;Vogels et al, 2003;Barouch et al, 2004;Wu and Tikoo, 2004;Abbink et al, 2007;Brouwer et al, 2007;Sakurai, 2008;McVey et al, 2010;Geisbert et al, 2011), HAdV-49 (Lemckert et al, 2006;Abbink et al, 2007), HAdV-26, -48, and -50 (Abbink et al, 2007;Geisbert et al, 2011), HAdV-7 (Nan et al, 2003), and HAdV-6 (Capone et al, 2006). However, since the presence of NAbs depends on AdV exposure, which is closely related to geographical location, seroprevalence studies in different specific populations are very important.…”