title: 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.
authors.affiliation: 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Brunetti-Pierri
authors.forename: Gary E
authors.initials: GE
authors.lastname: Stapleton
authors.forename: Mark
authors.initials: M
authors.lastname: Law
authors.forename: John
authors.initials: J
authors.lastname: Breinholt
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Palmer
authors.forename: Yu
authors.initials: Y
authors.lastname: Zuo
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Grove
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.forename: Karen
authors.initials: K
authors.lastname: Rice
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.forename: Charles E
authors.initials: CE
authors.lastname: Mullins
authors.forename: Philip
authors.initials: P
authors.lastname: Ng
mesh_terms: D000818:Animals; D002404:Catheterization / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics* / Q000633:toxicity; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000601:surgery*; D008297:Male; D010215:Papio; D014161:Transduction, Genetic / Q000379:methods*; D019076:Transgenes / Q000235:genetics*