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. To solve this, we used our innovative gene-editing platform to prototype four distinct model genotypes in pigs (PKD1R2220W/-; PKD1R3277C/-; PKD1+/R3277C and PKD1+/-), predicted to lower the level of functional polycystin-1 protein (PC1) to 10-50% of normal. We found severe disease in compound heterozygous founders, the first evidence that severe PKD can develop in pigs, whereas heterozygotes had very mild disease. We have established a breeding herd of PKD1+/R3277C and PKD1+/- from which we will breed two models, PKD1R3277C/- (RC-null) and PKD1R3277C/ R3277C (RC-RC). We will produce these two congenital models of ADPKD by standard breeding, and conduct initial analysis on newborn and sale-aged piglets (30 days) to determine the consistency of production and phenotype in the swine products. This 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 morphology, function, and the development of cysts. Results 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 testing. A second focus of this proposal is to generate a conditional model of ADPKD in a strain of miniature swine. This 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 progression, furthermore enabling preclinical evaluation to begin in the earliest phase of disease. The miniature size will also enable chronic studies to proceed past seven months of age where conventional swine outgrow clinical imaging equipment. The development and characterization very specific modified pigs, as described here, are likely to revolutionize ADPKD research and to fast-track treatment options. This is underscored by the tremendous industry support for a PKD model that provides a more rigorous preclinical testing platform.
This SBIR proposes to develop and characterize two models of polycystic kidney disease which could be a platform upon which therapies could be rigorously tested before entering human clinical trials. Such a model will provide the field of kidney disease with a much needed pre-clinical model that the FDA and industry strongly support.
