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（由申请方提供）：常染色体显性多囊肾病（ADPKD）是人类最常见的潜在致死性遗传疾病之一，发病率为1/500-1000。大多数ADPKD病例（85%）是由PKD 1基因突变引起的，该基因编码多囊蛋白-1。ADPKD是一种全身性疾病，通常导致肾衰竭和肾外表现，包括肝脏和胰腺囊肿、高血压、颅内动脉瘤、心脏瓣膜异常、主动脉夹层和腹壁疝的发展。尽管我们对这种疾病的理解取得了重大进展，但还没有批准的治疗方法来逆转或减缓ADPKD的进展。关于ADPKD的大部分知识来自对Pkd 1突变小鼠的研究。虽然直链小鼠模型对于理解疾病的某些方面非常有用，但它们不能概括人类疾病进展或其显性遗传，并且它们不能发展被认为是导致终末期肾病的重要因素的肾纤维化。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。也存在自然发生的犬和猫疾病模型，但它们的有效使用因解剖学差异、额外的非PKD表型、有限的可用性和社会接受问题而复杂化。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。我们建议在猪中建立ADPKD的改进模型。猪的解剖学、发育、生理学、遗传学和体型与人类的关系更为密切。事实上，猪已经被用于各种医学研究多年，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上级模型。因此，本项目的最终目标是开发和商业化PKD 1突变猪作为人类ADPKD模型。为了实现这一目标，将使用基因打靶和体细胞核移植来产生PKD 1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一个机会，以更有效地解决有关这种疾病及其发病机制的基本未回答的问题，并开发新的治疗方法和预防策略。