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常染色体显性遗传性结缔组织疾病(弹性蛋白)，主要影响心血管系统、眼睛和骨骼。发病率约为每9800名新生儿中就有1-2名，这对患者的一生来说是一个重大的医学挑战。特征包括进行性主动脉扩张伴瓣膜关闭不全、二尖瓣脱垂和关闭不全、晶状体脱位伴近视、四肢长而瘦的身体结构，以及有时未经治疗的脊柱侧弯。成人形式的马凡氏综合征平均年龄为32岁，当主动脉扩张达到或超过5.5厘米时，会导致升主动脉破裂和/或夹层。为了加强翻译工作，开发手术和非手术方法来缓解马凡氏综合症，需要建立一个大的马凡综合征动物模型。此前，已经在小鼠身上证明，操纵导致马凡氏综合症的基因(FBN1)可以产生马凡氏综合症的动物模型。虽然小鼠模型对血管紧张素II 1型受体(AT1)阻滞剂等药物的评估很有用，但还需要更多的模型，既能确认小鼠的数据，又能开发新的手术方法。马凡的猪模型多年来一直是一个目标，但直到最近，开发这些复杂的转基因猪所需的技术才发展到足以在预算和所要求的时间框架内提出这样的建议。我们建议通过灭活和修饰该物种中的FBN1基因来建立猪的马凡综合征模型。一旦被开发出来，转基因动物的心血管、骨骼和眼睛系统将被广泛地表征，以确定它们作为人类马凡动物模型的有效性。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这种毁灭性的疾病。

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.