Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, potentially fatal genetic disorders in humans with an incidence of 1 in every 500-1000 individuals. The majority of ADPKD cases (85%) are caused by mutations in the PKD1 gene, which encodes polycystin-1. ADPKD is a systemic disorder that often leads to kidney failure and extrarenal manifestations including the development of cysts in the liver and pancreas, hypertension, intracranial aneurysms, cardiac valve abnormalities, aortic dissection, and abdominal wall hernias. Despite significant progress in our understanding of this disease, there are no approved treatments to reverse or slow the progression of ADPKD. Much of what is known about ADPKD has come from studying Pkd1 mutant mice. While the orthologous murine models have been very useful for understanding some aspects of the disease, they do not recapitulate human disease progression or its dominant inheritance, and they fail to develop the renal fibrosis that is thought to be a significant factor leading to end stage renal disease. Furthermore, therapeutic strategies that have shown promise in these models have not yet been successfully translated to patients. Naturally occurring canine and feline disease models also exist, however their effective use is complicated by differences in anatomy, additional non-PKD phenotypes, limited availability, and social acceptance concerns. An animal model that more accurately and consistently replicates the clinical phenotype of human ADPKD is necessary to bridge the gap between models currently used for early stage drug discovery and human clinical trials. We propose to create an improved model of ADPKD in the pig. Porcine anatomy, development, physiology, genetics, and size are more closely related to that of humans. Indeed, pigs have been used for years in a variety of medical studies, and recent application of gene targeting and cloning technologies to pigs has produced superior models of several human genetic diseases. Therefore, the ultimate goal of this project is to develop and commercialize PKD1-mutant pigs as a model of human ADPKD. To accomplish this, gene targeting and somatic cell nuclear transfer will be used to produce PKD1-mutant pigs, followed by a brief characterization. Subsequent Phase II activities will further characterize and validate the model. This project will generate a new model of ADPKD in the pig and provide academic and industry researchers with an opportunity to more effectively address fundamental, unanswered questions regarding this disease and its pathogenesis and to develop new therapeutics and preventative strategies.
This project will develop a new porcine model of autosomal dominant polycystic kidney disease, and thereby provide a resource to stimulate discovery and the development of new therapeutics and preventative strategies.
|Rogers, Christopher S (2016) Engineering Large Animal Species to Model Human Diseases. Curr Protoc Hum Genet 90:15.9.1-15.9.14|