Novel Transgenic Rabbit Model for Cardiovascular Disease

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DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the single most common cause of death in the United States. Although the study of the CVD has greatly benefited from the use of gene-targeted transgenic mouse models, these small rodents do not accurately reflect human cardiovascular physiology. The Rabbit would be an excellent animal model for CVD research, considering its many similarities to humans in cardiovascular anatomy, physiology, and lipid metabolism. The long term goal of Evergen is to establish a facility that provides researchers in the biomedical and pharmaceutical community with gene targeted transgenic rabbits. In this project, Evergen Biotechnologies, Inc. proposes to use an approach by combining the proprietary somatic cell nuclear transfer and the gene-targeting technologies to produce the first gene-targeted transgenic rabbits as CVD and other human disease models for the study of the disease mechanisms and development of therapies. In this project, we propose to produce Cholesterol Ester Transfer Protein (CETP) knockout rabbits. So far, several companies including Pfizer, Merck, Roche, and Japan Tobacco have developed drugs targeting on human CETP. The recent unfavorable clinical trials of Pfizer's CETP inhibitor, Torcetrapib urged researchers in this field to provide a better animal model system to understand the CETP functions and effects of drugs targeting on CETP. In Phase I, we propose to target CETP gene in rabbit fibroblast cells and produce CETP knockout cells (CETP). We will then use these cells for nuclear transfer to produce CETP KO (CETP) embryos. In Phase II, we will first focus on the production of CETP knockout (CETP) rabbits. We will breed CETP KO rabbits with Hepatic Lipase transgenic rabbits to generate humanized CETP KO rabbits. Hepatic Lipase activity is much lower in normal rabbits than in human. Finally we will perform the pathology evaluation of the humanized CETP KO rabbits. We are confident that through the proposed project, a feasible method to produce gene targeted transgenic rabbits will be developed and we will for the first time provide a knockout rabbit model to the researchers worldwide.