Development of a Swine Model of Marfan Syndrome

描述（由申请人提供）： 马凡氏综合征是一种可变的常染色体显性结缔组织疾病（弹性蛋白），主要影响心血管系统，眼睛和骨骼。发生率约为1-2/9800，对患者的一生都是一个重大的医学挑战。其特征包括与瓣膜关闭不全相关的进行性主动脉扩张、二尖瓣脱垂和关闭不全、与近视相关的透镜脱位、四肢长的高瘦身体结构，有时脊柱侧凸未经治疗，当主动脉扩张达到或超过5.5cm并导致破裂和/或破裂时，成人形式的马凡氏综合征的死亡率发生在平均32岁。或升主动脉夹层为了加强开发手术和非手术方法以减轻马凡氏综合征的转化努力，需要该疾病的大型动物模型。以前，已经在小鼠中证明，操纵负责马凡氏综合征的基因（FBN 1）可以产生马凡氏综合征的动物模型。虽然小鼠模型可用于评价血管紧张素II 1型受体（AT 1）阻滞剂等药物，但仍需要其他模型，既可确认小鼠数据，又可开发新的手术方法。多年来，马凡氏病猪模型一直是一个目标，但直到最近，开发这些复杂的转基因猪所需的技术才得到充分发展，使这样的建议在预算和要求的时间范围内成为现实。我们建议通过灭活和修饰该物种的FBN 1基因来建立马凡氏综合征的猪模型。一旦开发出转基因动物的心血管、骨骼和眼部系统，将对其进行广泛表征，以确定其作为人类马凡氏动物模型的有效性。这种动物模型的成功开发将导致开发新的手术和非手术方法来治疗人类的这种破坏性疾病。

DESCRIPTION (provided by applicant): 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.