Pre-clinical study of gene therapy against refractory diseases in animals.

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The object of this study is the development of gene therapy against tumors and immune-abnormalities in veterinary field. In this research period, the study of 1) basic research of gene therapy by hepatocyte growth factor (HGF), 2) construction of adenovirus vector containing canine p53 and its effects for canine tumor cell lines, 3) gene therapy for and by feline immunodeficiency virus (FIV), have been conducted.1) HGF-gene therapy for liver and renal insufficiency in dogs and cats : Feline and canine HGF cDNA were cloned and their expressions were examined in various liver diseases in dogs together with tumor transforming growth factor (TGF). Furthermore, feline and canine HGF cDNA was inserted into expression plasmid and their efficient gene delivery method was examined.2) Gene therapy for tumors in dogs and cats : Aberrations of the p53 tumor suppressor gene in various tumors in dogs was investigated together with the abnormalities of centrosome. We next constructed adenovirus vector expressing canine p53 which was cloned in our laboratory and examined its cytocidal effects on canine tumor cell lines. Furthermore, feline IL-18 cDNA was cloned and expression plasmid for canine CTLA-4 fusion protein to enhance anti-tumor immunity.3) Gene therapy for FIV infection : We developed the novel method to quantify FIV RNA in plasma and an association of plasma viral RNA load with prognosis in cats naturally infected with FIV was investigated. We also investigated the mechanism of apoptosis of FIV-infected cells and cloned feline TNF receptors. Furthermore, feline vascular endotherial growth factor (VEGF) cDNA was cloned to develop new gene therapy against FIV infection.