Pseudo-hydrodynamic delivery of helper-dependent adenoviral vectors into non-human primates for liver-directed gene therapy.
Helper-dependent adenoviral vectors (HDAds) are attractive for liver-directed gene therapy because they can mediate long-term, high-level transgene expression without chronic toxicity. However, systemic delivery requires high vector doses for efficient hepatic transduction, resulting in dose-dependent acute toxicity. Clearly, strategies to improve hepatic transduction with low vector doses are needed. In this regard, we have previously shown that hydrodynamic injection of helper-dependent adenoviral vectors into mice results in increased hepatic transduction, reduced systemic vector dissemination, and reduced pro-inflammatory cytokines compared with conventional injection and thus has the potential to improve dramatically the therapeutic index of helper-dependent adenoviral vectors. Unfortunately, the rapid, large-volume injection used in this method cannot be applied to larger animals. Therefore, we have developed a novel balloon occlusion catheter-based method to mimic hydrodynamic injection of helper-dependent adenoviral vectors into non-human primates that does not require rapid, large-volume injection. Using a low, clinically relevant vector dose, this minimally invasive method results in high-efficiency hepatic transduction with minimal toxicity and stable long-term transgene expression for at least 413 days.
Brunetti-Pierri
Nicola
N
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Stapleton
Gary E
GE
Palmer
Donna J
DJ
Zuo
Yu
Y
Mane
Viraj P
VP
Finegold
Milton J
MJ
Beaudet
Arthur L
AL
Leland
Michelle M
MM
Mullins
Charles E
CE
Ng
Philip
P
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006378:Helper Viruses / Q000235:genetics; D007267:Injections; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010215:Papio; D013997:Time Factors