Development of a drug therapy to treat polycystic kidney disease (PKD) is proposed. PKD is the most common human genetic disease affecting approximately one half million people in the USA. The over-expression of the proto-oncogene c-myc has been shown to be integral to cyst development in rodent PKD models which mimic the human disease. We propose the hypothesis that inhibition of c-myc expression using phosphorodiamidate morpholino oligonucleotides (PMOs) complementary to c-myc mRNA AUG translation start site (AVI-4126) will stop or slow progression of PKD. This compound is currently in preclinical development for use in the treatment of osteogenic sarcoma and restinosis. The use of AVI-4126 in the treatment of PKD is a novel approach to a disease for which there are currently no effective drugs for treatment of the underlying disease. Preliminary results with AVI-4126 in a mouse model of human disease suggests both safety and efficacy. We propose studies outlined by the following four aims: l) Evaluate the ability of PMOs to gain access to the appropriate cells of the renal cyst epithelium, 2.) Evaluation of inhibition of c-myc by antisense PMOs in C57BL/6J-cpk mice, and 3.) Evaluation of inhibition of c-myc by antisense PMOs in Balb-c-cpk mice 4.) Evaluation of inhibition of c-myc by antisense PMOs in Han:SPRD rats. The proposed research, if successful, would lead to a proposal for Phase II funding to bring the use of AVI-4126 into the drug market.
The studies outlined in this proposal are designed to test a compound currently being evaluated for restinosis and osteogenic sarcoma in a model of PKD. The intent of this proposal is to test the feasibility of bringing AVI-4126 or other antisense compounds into the drug market and provide an inexpensive alternative to invasive palliative procedures for PKD treatment. Evidence of efficacy in Phase I will lead to a proposal for preclinical development in Phase Il.
