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

 描述(申请人提供)：多囊肾疾病(PKD)是一组遗传性疾病，其特征是肾脏内逐渐发展的囊性病变，导致双侧肾脏增大，通常是终末期肾脏疾病(ESRD)。PKD的最常见形式是常染色体显性遗传性PKD，发生频率为1：400至1：1000。目前，还没有一种治疗方法可以减缓或逆转包囊的生长和疾病的发展。虽然已经开发了小鼠模型来表征PKD的病理和进展，但它们往往不能很好地指示人类的治疗成功。我们建议开发两种特定的PKD基因敲入模型，与在人类疾病发展中观察到的基因变化紧密匹配。这些猪模型将使用Recombinetics使用TALEN技术对牲畜进行基因编辑的独家许可证进行开发。最终得到的猪将被评估肾脏的形态、功能和囊性病变的发展，并与患者的PKD的病理和发展进行比较。这些模型的开发可能会给PKD研究带来革命性的变化，并基于严格的临床前试验快速追踪治疗方案。PKD发展的证据与人类疾病非常相似，这将证明在第二阶段拨款中进行详细评估是合理的，并为在临床前试验中使用该模型制定标准操作程序。

 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.