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The Safety of Adenovirus-Mediated Antisense c-myc Infused into Hepatic Artery or Portal Vein in Beagle Dogs
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Abstract:
Objective: To assess the preclinical safety of recombinant adenovirus-mediated antisense c-myc infustion of the hepatic vascular of Beagle dogs. Methods: Four 8 to 10 kg healthy Beagle dogs underwent hepatic artery or portal vein cannulation infusion of 1×10 10～1×10 11 plaque forming units recombinant adenovirus vectors. Serial sequenced liver biopsies were taken for microscopic examination and PCR analysis. Venous blood samples were obtained from the dogs for liver, renal function tests and hematology analysis after infusion of days 0, 3, 7, 14, and 21. PCR was used to screen the vital organs for the presence of adenovirus DNA. Microscopic examination of the vital organs was performed to observe the pathogenicity of Ad-ASmyc. ELISA was performed to assay the neutralizing antibody to adenovirus vectors. Results：Ad-ASmyc could infect both kinds of normal human fetal lung cell line 2BS and normal human hepatocyte line L02 effectively, but could not inhibit their growth in vitro. Results of liver, renal function and hematology values were within normal ranges. The adenovirus vectors were present in the liver, spleen, heart, kidney, stomach and skin at days 14 or 21. Microscopic examination revealed no cytopathic effects in distant organs, as was gross pathology, despite the presence of vector. Ad-ASmyc was transferred into hepatocytes persistently and induced dose-dependent inflammation response. Production of anti-adenovirus antibodies appeared at days 7, reached high-level at days 14 and declined at days 21.Conclusions：Ad-ASmyc can be transferred into hepatocellulars via hepatic artery or portal vein and generates no obvious toxicity in Beagle dogs, which suggests the safety of Ad-ASmyc infused into the hepatic vascular for gene therapy.
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Clc Number:
R730.5
