Development of a Porcine Model of Autosomal Dominant Polycystic Kidney Disease

描述（由申请人提供）：常染色体显性多囊肾病（ADPKD）是人类最常见、潜在致命的遗传性疾病之一，发病率为每500-1000人中有1人。大多数ADPKD病例（85%）是由编码多囊蛋白-1的PKD1基因突变引起的。ADPKD是一种全身性疾病，常导致肾衰竭和肾外表现，包括肝和胰腺囊肿的发展、高血压、颅内动脉瘤、心瓣膜异常、主动脉夹层和腹壁疝。尽管我们对这种疾病的理解取得了重大进展，但目前还没有批准的治疗方法来逆转或减缓ADPKD的进展。我们对ADPKD的了解大多来自于对Pkd1突变小鼠的研究。虽然同源小鼠模型对于了解疾病的某些方面非常有用，但它们不能概括人类疾病的进展或其主要遗传，并且它们不能发展肾纤维化，而肾纤维化被认为是导致终末期肾脏疾病的重要因素。此外，在这些模型中显示出希望的治疗策略尚未成功地转化为患者。自然发生的犬和猫疾病模型也存在，但是它们的有效使用由于解剖学的差异、额外的非pkd表型、有限的可用性和社会接受问题而变得复杂。一个更准确和一致地复制人类ADPKD临床表型的动物模型对于弥合目前用于早期药物发现和人类临床试验的模型之间的差距是必要的。我们建议在猪身上建立一种改良的ADPKD模型。猪的解剖、发育、生理、遗传和体型与人类更接近。事实上，多年来猪一直被用于各种医学研究，最近基因靶向和克隆技术在猪身上的应用已经产生了几种人类遗传疾病的优越模型。因此，该项目的最终目标是开发和商业化pkd1突变猪作为人类ADPKD的模型。为了实现这一目标，基因靶向和体细胞核转移将用于生产pkd1突变猪，然后进行简短的表征。随后的第二阶段活动将进一步描述和验证该模型。该项目将产生猪ADPKD的新模型，并为学术和行业研究人员提供一个机会，更有效地解决有关该疾病及其发病机制的基本问题，并开发新的治疗方法和预防策略。

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, potentially fatal genetic disorders in humans with an incidence of 1 in every 500-1000 individuals. The majority of ADPKD cases (85%) are caused by mutations in the PKD1 gene, which encodes polycystin-1. ADPKD is a systemic disorder that often leads to kidney failure and extrarenal manifestations including the development of cysts in the liver and pancreas, hypertension, intracranial aneurysms, cardiac valve abnormalities, aortic dissection, and abdominal wall hernias. Despite significant progress in our understanding of this disease, there are no approved treatments to reverse or slow the progression of ADPKD. Much of what is known about ADPKD has come from studying Pkd1 mutant mice. While the orthologous murine models have been very useful for understanding some aspects of the disease, they do not recapitulate human disease progression or its dominant inheritance, and they fail to develop the renal fibrosis that is thought to be a significant factor leading to end stage renal disease. Furthermore, therapeutic strategies that have shown promise in these models have not yet been successfully translated to patients. Naturally occurring canine and feline disease models also exist, however their effective use is complicated by differences in anatomy, additional non-PKD phenotypes, limited availability, and social acceptance concerns. An animal model that more accurately and consistently replicates the clinical phenotype of human ADPKD is necessary to bridge the gap between models currently used for early stage drug discovery and human clinical trials. We propose to create an improved model of ADPKD in the pig. Porcine anatomy, development, physiology, genetics, and size are more closely related to that of humans. Indeed, pigs have been used for years in a variety of medical studies, and recent application of gene targeting and cloning technologies to pigs has produced superior models of several human genetic diseases. Therefore, the ultimate goal of this project is to develop and commercialize PKD1-mutant pigs as a model of human ADPKD. To accomplish this, gene targeting and somatic cell nuclear transfer will be used to produce PKD1-mutant pigs, followed by a brief characterization. Subsequent Phase II activities will further characterize and validate the model. This project will generate a new model of ADPKD in the pig and provide academic and industry researchers with an opportunity to more effectively address fundamental, unanswered questions regarding this disease and its pathogenesis and to develop new therapeutics and preventative strategies.