title: Safety assessment of liver-targeted hydrodynamic gene delivery in dogs.
abstract: Evidence in support of safety of a gene delivery procedure is essential toward gene therapy. Previous studies using the hydrodynamics-based procedure primarily focus on gene delivery efficiency or gene function analysis in mice. The current study focuses on an assessment of the safety of computer-controlled and liver-targeted hydrodynamic gene delivery in dogs as the first step toward hydrodynamic gene therapy in clinic. We demonstrate that the impacts of the hydrodynamic procedure were limited in the injected region and the influences were transient. Histological examination and the hepatic microcirculation measurement using reflectance spectrophotometry reveal that the liver-specific impact of the procedure involves a transient expansion of the liver sinusoids. No systemic damage or toxicity was observed. Physiological parameters, including electrocardiogram, heart rate, blood pressure, oxygen saturation, and body temperature, remained in normal ranges during and after hydrodynamic injection. Body weight was also examined to assess the long-term effects of the procedure in animals who underwent 3 hydrodynamic injections in 6 weeks with 2-week time interval in between. Serum biochemistry analysis showed a transient increase in liver enzymes and a few cytokines upon injection. These results demonstrate that image-guided, liver-specific hydrodynamic gene delivery is safe.
authors.affiliation: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Kamimura
authors.affiliation: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kanefuji
authors.affiliation: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yokoo
authors.affiliation: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Abe
authors.affiliation: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suda
authors.affiliation: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Guisheng
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Aoyagi
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Dexi
authors.initials: D
authors.lastname: Liu
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000097:blood; D004285:Dogs; D004562:Electrocardiography; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D057446:Hydrodynamics; D007267:Injections / Q000009:adverse effects / Q000379:methods; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008102:Liver Circulation; D008991:Monitoring, Physiologic; D015203:Reproducibility of Results; D018570:Risk Assessment; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D018932:Chemokine CCL2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10