Development of a Porcine Model of Autosomal Dominant Polycystic Kidney Disease

常染色体显性多囊肾病猪模型的建立

• 批准号: 8645916
• 负责人: Christopher Rogers
• 金额: $ 23.89万
• 依托单位: EXEMPLAR GENETICS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645916
• 关键词: Address; Alleles; Anatomy; Animal Model; Autosomal Dominant Polycystic Kidney; Cat Diseases; Cell Line; Cells; Clinical Trials; Cyst; Development; Disease; Disease Progression; Disease model; Dissection; Dog Diseases; End stage renal failure; Family suidae; Fibroblasts; Fibrosis; Gene Targeting; Genetic; Goals; Heart Valves; Hereditary Disease; Hernia; Human; Human Genetics; Hypertension; Incidence; Individual; Industry; Intracranial Aneurysm; Kidney; Kidney Failure; Liver; Medical; Modeling; Mus; Mutant Strains Mice; Mutation; Newborn Infant; Nuclear; PKD1 gene; Pancreas; Pathogenesis; Patients; Phase; Phenotype; Physiology; Research Personnel; Resources; Staging; Technology; Testing; Therapeutic; Translating; Validation; abdominal wall; clinical phenotype; cost; drug discovery; fetal; gene cloning; homologous recombination; human disease; improved; mutant; novel therapeutic intervention; novel therapeutics; polycystic kidney disease 1 protein; public health relevance; social; somatic cell nuclear transfer

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.

描述（由申请人提供）：常染色体显性多囊性肾脏疾病（ADPKD）是人类中最常见的，潜在的致命遗传疾病之一，每500-1000名患者中有1例。大多数ADPKD病例（85％）是由PKD1基因中的突变引起的，该基因编码了Polycystin-1。 ADPKD是一种全身性疾病，通常导致肾衰竭和肾外表现，包括肝脏和胰腺中囊肿的发展，高血压，颅内动脉瘤，心脏瓣膜异常，主动脉神解和腹部壁源泉。尽管我们对这种疾病的理解取得了重大进展，但尚无批准的治疗方法来扭转或减缓ADPKD的发展。关于ADPKD的许多知识来自研究PKD1突变小鼠。虽然直系同源的鼠模型对于理解疾病的某些方面非常有用，但它们并未概括人类疾病的进展或其主要遗传，并且未能发展出肾纤维化，这被认为是导致终阶段肾脏疾病的重要因素。此外，在这些模型中表现出希望的治疗策略尚未成功地转化为患者。天然发生的犬类和猫科疾病模型也存在，但是它们的有效使用使解剖学的差异，其他非PKD表型，有限的可用性和社会接受度问题变得复杂。更准确，更始终如一地复制人ADPKD的临床表型的动物模型对于弥合当前用于早期药物发现和人类临床试验的模型之间的差距。我们建议在猪中创建改进的ADPKD模型。猪解剖学，发育，生理，遗传学和大小与人类的相关性更紧密。实际上，猪已经在各种医学研究中使用了多年，并且最近将基因靶向和克隆技术应用于猪已经产生了几种人类遗传疾病的卓越模型。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。为此，基因靶向和体细胞核转移将用于产生PKD1突变猪，然后进行简短的表征。随后的II期活动将进一步表征和验证模型。该项目将在猪中产生一种新的ADPKD模型，并为学术和行业研究人员提供更有效地解决有关该疾病及其发病机理的基本，未解决的问题，并制定新的治疗疗法和预防策略。