Efficient, Long-term Hepatic Gene Transfer Using Clinically Relevant HDAd Doses by Balloon Occlusion Catheter Delivery in Nonhuman Primates

Abstract

Helper-dependent adenoviral vectors (HDAd) are devoid of all viral coding sequences and are thus an improvement over early generation Ad because they can provide long-term transgene expression in vivo without chronic toxicity. However, high vector doses are required to achieve efficient hepatic transduction by systemic intravenous injection, and this unfortunately results in dose-dependent acute toxicity. To overcome this important obstacle, we have developed a minimally invasive method to preferentially deliver HDAd into the liver of nonhuman primates. Briefly, a balloon occlusion catheter was percutaneously positioned in the inferior vena cava to occlude hepatic venous outflow. HDAd was injected directly into the occluded liver via a percutaneously placed hepatic artery catheter. Compared to systemic vector injection, this approach resulted in substantially higher hepatic transduction efficiency using clinically relevant low vector doses and was accompanied by mild-to-moderate acute but transient toxicities. Transgene expression was sustained for up to 964 days. These results suggest that our minimally invasive method of delivery can significantly improve the vector's therapeutic index and may be a first step toward clinical application of HDAd for liver-directed gene therapy.

Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors

“…Rapid elevation in IL-6 or TNF-a indicates an acute inflammatory response and these cytokines may be sensitive markers of clinical or subclinical adenovirus toxicity. 23,[27][28][29][30] However, no significant increase in any of analyzed cytokines occurred in our patient cohort. This suggests that Ad5/3-Cox2L-D24, at the doses used here, did not induce acute systemic toxicity responses.…”

Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia

“…11 Baboons and mice given a single dose of an HDAd vector had appreciable hepatic transgene expression, lasting 1-2.5 years. [11][12][13][14][15] Because of the long-term transgene expression and relatively low toxicity, in comparison with first generation Ad vectors, HDAd vectors present an attractive candidate for the development of gene therapy for inherited disorders such as GSD-Ia.…”

The Role of Liver Sinusoidal Cells in Hepatocyte-Directed Gene Transfer

“…Recently, Brunetti-Pierri et al 54 developed a minimally invasive procedure that significantly improves the efficiency of hepatocyte-directed transfer in nonhuman primates. A balloon occlusion catheter was percutaneously positioned in the inferior vena cava to occlude hepatic venous outflow.…”

“…A balloon occlusion catheter was percutaneously positioned in the inferior vena cava to occlude hepatic venous outflow. 54 Gene transfer of gutted vectors was performed via a percutaneously placed hepatic artery catheter with an infusion time of 7.5 or 15 minutes. This procedure resulted in ϳ10-fold higher transgene expression levels compared with systemic gene transfer.…”