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

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 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.