Development of Porcine Genetic Models of Atherosclerosis

DESCRIPTION (provided by applicant): Because the cardiovascular anatomy of swine is similar to humans with regard to size, morphology, relative collateral arterial supply, and the presence of a well-developed vasa vasorum, the porcine coronary arterial model is the standard for the preclinical evaluation of endovascular devices. Indeed, a consensus report concerning FDA approval of the stents recommends the use of the pig model to assess these devices. However, a marked deficiency in current pig models is that they do not present with metabolic syndrome and significant atherosclerosis, underlying conditions that can drastically alter restenosis and thrombosis. Thus, the development of efficacious and safe stents continues to be confounded by the absence of asufficient large animal model of atherosclerosis. The ideal pig model would be of manageable size and manifest both metabolic syndrome and atherosclerosis at an early age. Like mice, the pig genome can be efficiently manipulated to create hypomorphic andnull alleles by genome engineering. In this Phase 1 STTR we propose to generate a pig model of metabolic syndrome and rapid atherosclerosis by knocking out the low density lipoprotein receptor gene in a strain of minipigs (Ossabaw) with a genetic propensity for Type 2 diabetes. A strategy employing sequential gene targeting by homologous recombination using adeno-associated virus, and iterative cloning by somatic cell nuclear transfer will result in the generation of LDLR-null minipigs during this Phase I STTR. Successful creation of OssabawLDLR -/- minipigs with evidence of enhanced dyslipidemia would justify submission of a Phase II STTR proposal focused on herd expansion, in-depth physiological characterization, and potentially commercialization of the model for sales to the biomedical research community. PUBLIC HEALTH RELEVANCE: This STTR proposes to create a pig model of metabolic syndrome and rapid atherosclerosis by knocking out the low density lipoprotein receptor (LDLR) gene in the Ossabaw minipig. Using a novel accelerated approach to gene inactivation, pigs without the LDLR gene will be generated during this Phase 1 STTR and their lipid profile will be examined for evidence of disrupted lipid processing. These pigs will be further characterized on the basis of subsequent funding, and if evidence of accelerated atherosclerosis is found, a population of pigs will be generated and provided for sale to the biomedical research community.