Development of a porcine model of polycystic kidney disease by multiplex gene-editing.

 描述（由申请人提供）：多囊肾病（PKD）是一组遗传性疾病，其特征为肾脏进行性囊肿发育，导致双侧肾脏增大，通常为终末期肾病（ESRD）。PKD的最常见形式，常染色体显性PKD以1：400至1：1000的频率发生。目前，没有治疗方法可以减缓或逆转囊肿的生长和疾病的进展。虽然已经开发了小鼠模型来表征PKD的病理和进展，但它们往往是人类治疗成功的不良指标。我们建议开发两种特定的PKD基因敲入模型，与人类疾病发展中观察到的遗传变化密切匹配。这些猪模型将使用TALEN技术在牲畜中进行基因编辑的独家许可证开发。将评价所得猪的肾脏形态、功能和囊肿的发展，并与患者中PKD的病理学和发展进行比较。这些模型的开发可能会彻底改变PKD研究，并基于严格的临床前测试快速跟踪治疗方案。PKD发展与人类疾病非常相似的证据将证明在II期资助中进行详细评估以及开发用于临床前测试的模型的标准操作程序是合理的。

 DESCRIPTION (provided by applicant): Polycystic kidney diseases (PKD) are a group of inherited disorders characterized by progressive cyst development in the kidney resulting in bilateral renal enlargement and often end stage renal disease (ESRD). The most common form of PKD, autosomal dominant PKD occurs at a frequency of 1:400 to 1:1000. Currently, there is no treatment that can slow or reverse the growth of cysts and progression of the disease. While mouse models have been developed to characterize the pathology and progression of PKD, they tend to be poor indicators of therapeutic success in humans. We propose to develop two specific knock-in models of PKD, closely matching the genetic changes observed in human disease development. These pig models will be developed using Recombinetics exclusive license for gene-editing in livestock using TALEN technology. The resulting pigs will be evaluated for renal morphology, function, and the development of cysts, and compared to the pathology and development of PKD in patients. The development of these models is likely to revolutionize PKD research and to fast-track treatment options based on rigorous preclinical testing. Evidence of PKD development that closely resembles the human disease will justify detailed assessment in a Phase II grant and development of standard operating procedures for use of the model in preclinical testing.