? Marfan's Syndrome is a variable, autosomal dominant connective tissue disorder (elastin), affecting mainly the cardiovascular system, eyes, and skeleton. The occurrence is approximately 1-2 in 9800 births and represents a significant medical challenge for the patient throughout life. The characteristic features include progressive aortic dilation associated with valve incompetence, mitral valve prolapse and incompetence, lens dislocation with associated myopia, and a tall and thin body structure with long limbs, and at times scoliosis Untreated, mortality in adult form of Marfan's Syndrome occurs at average age of 32 years when aortic dilatation reaches or exceeds 5.5 cm and results in rupture and/or dissection of the ascending aorta. In order to enhance translational efforts to develop surgical and non-surgical methods to alleviate Marfan syndrome, a large animal model of the disease is needed. Previously, it has been demonstrated in mice that manipulation of the gene (FBN1) responsible for Marfan syndrome can generate an animal model of Marfan syndrome. While the mouse model has been useful for the evaluation of drugs such as Angiotensin II type 1 receptor (AT1) blockers, there is a need for additional models that can both confirm the mouse data as well as allow development of new surgical approaches. A swine model of Marfan has been a goal for many years but it is only recently that the technology required to develop these complex transgenic pigs has developed sufficiently to make a proposal such as this realistic within the budget and the time frame requested. We propose to develop swine models of Marfan syndrome by inactivation and modification of the FBN1 gene in this species. Once developed the cardiovascular, skeletal, and ocular systems in the genetically modified animals will be extensively characterized to determine their validity as animal models of human Marfan. Successful development of this animal models will results in the development of n novel surgical and non-surgical approaches to treat this devastating conditions in humans. ? ? ? ?