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

PROJECT SUMMARY Polycystic kidney diseasesPKDare a group of inherited disorders characterized by progressive cyst development in the kidney resulting in bilateral renal enlargement and often end stage renal diseaseESRDThe most common form of PKDautosomal dominant PKD occurs at a frequency oftoCurrentlythere is no treatment that can slow or reverse the growth of cysts and progression of the diseaseWhile mouse models have been developed to characterize the pathology and progression of PKDthey tend to be poor indicators of therapeutic success in humansTo solve thiswe used our innovative gene editing platform to prototype four distinct model genotypes in pigsPKD RWPKD RCPKDRC and PKDpredicted to lower the level of functional polycystinproteinPCtoof normalWe found severe disease in compound heterozygous foundersthe first evidence that severe PKD can develop in pigswhereas heterozygotes had very mild diseaseWe have established a breeding herd of PKDRC and PKDfrom which we will breed two modelsPKD RCRC nulland PKD RCRCRC RCWe will produce these two congenital models of ADPKD by standard breedingand conduct initial analysis on newborn and sale aged pigletsdaysto determine the consistency of production and phenotype in the swine productsThis analysis will be followed with state of the art clinical imaging procedures extending to seven months of age with concordant clinical chemistries to evaluate renal morphologyfunctionand the development of cystsResults from these studies will be compared to the pathology and development of PKD in patients and will benchmark the progression of disease in our novel models in a setting consistent with their use in preclinical testingA second focus of this proposal is to generate a conditional model of ADPKD in a strain of miniature swineThis strain will build on the ADPKD product line with the unique ability to induce disease development shortly after birth for real time analysis of disease progressionfurthermore enabling preclinical evaluation to begin in the earliest phase of diseaseThe miniature size will also enable chronic studies to proceed past seven months of age where conventional swine outgrow clinical imaging equipmentThe development and characterization very specific modified pigsas described hereare likely to revolutionize ADPKD research and to fast track treatment optionsThis is underscored by the tremendous industry support for a PKD model that provides a more rigorous preclinical testing platform