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

通过多重基因编辑开发多囊肾病猪模型。

• 批准号: 8834692
• 负责人: Daniel Fred Carlson
• 金额: $ 35.24万
• 依托单位: RECOMBINETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834692
• 关键词: Adult; Age-Months; Alleles; Anatomy; Animals; Arts; Autopsy; Autosomal Dominant Polycystic Kidney; Bilateral; Biochemistry; Blood Chemical Analysis; Blood Tests; Breeding; Clinic; Clinical; Clinical Trials; Cloning; Complex; Cyst; DNA; Development; Disease; Disease Progression; End stage renal failure; Evaluation; Exons; Family suidae; Fibroblasts; Founder Generation; Frequencies; Gene Targeting; Generations; Genes; Genetic; Genotype; Grant; Growth; Heterozygote; Histopathology; Human; Impairment; Inborn Genetic Diseases; Industry; Investigation; Kidney; Kidney Diseases; Kidney Transplantation; Knock-in Mouse; Laboratories; Licensing; Livestock; Measures; Mediating; Modeling; Monitor; Morphology; Mutation; Newborn Infant; PKD1 gene; Pathology; Patients; Phase; Physiology; Polycystic Kidney Diseases; Pre-Clinical Model; Preclinical Testing; Procedures; Production; Proteins; Renal Replacement Therapy; Renal function; Research; Rodent; Rodent Model; Small Business Innovation Research Grant; System; Technology; Testing; Therapeutic; Ultrasonography; aged; base; comparative; cost; dosage; embryonic stem cell; fetal; functional disability; human disease; innovation; loss of function; model development; mouse model; mutant; novel; polycystic kidney disease 1 protein; public health relevance; repaired; response; success; therapeutic target; urologic; vector

 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.

 描述（由申请人提供）：多囊肾病（PKD）是一组遗传性疾病，其特征是肾脏中进行性囊肿发展，导致双侧肾脏肿大，并且常常导致终末期肾病（ESRD）。常染色体显性 PKD 是 PKD 最常见的形式，发生频率为 1:400 至 1:1000。目前，没有任何治疗方法可以减缓或逆转囊肿的生长和疾病的进展。虽然已经开发出小鼠模型来表征 PKD 的病理学和进展，但它们往往不能作为人类治疗成功的指标。我们建议开发两种特定的 PKD 敲入模型，与人类疾病发展中观察到的基因变化紧密匹配。这些猪模型将利用 Recombinetics 的独家许可进行开发，该许可使用 TALEN 技术对牲畜进行基因编辑。将评估所得猪的肾脏形态、功能和囊肿的发育，并与患者 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，并根据严格的临床前测试快速制定治疗方案。 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以及制定在临床前测试中使用该模型的标准操作程序是合理的。