ADPKD is characterized by the presence of numerous fluid-filled cysts, which grow in size over time and produce kidney failure. Despite recent progress, pathogenesis of ADPKD is not fully understood, and no FDA-approved drugs are available. Majority of ADPKD patients develop cysts due to complete loss-of- function of PKD1 or 2. However, new evidence indicates that some ADPKD patients harbor hypomorphic mutations, and they develop cysts due to reduced PKD1 or 2 gene dosage. Another new theme is that reduced dosage of several gene products within the `cystic pathway' aggravates the ADPKD phenotype. These observations suggest that improving the expression of PKD1, PKD2 and other `cystic pathway genes' represents an exciting new therapeutic opportunity to suppress cyst growth. miRNAs are unique drug targets in this regard as they can be inhibited to simultaneously increase the expression of multiple cystic pathway genes. RATIONALE: The role of miRNAs in ADPKD largely remains unexplored. We have recently showed that: (i) miR-17~92 is up-regulated in models of PKD; (ii) kidney-specific overexpression of miR-17~92 in normal mice produces cysts; and (iii) importantly, inhibition of miR-17~92 in a mouse model of PKD suppresses cyst growth. Interestingly, many cystic kidney disease genes are predicted to be miR-17~92 targets. Thus, inhibition of the miR-17~92 may be a potential new therapeutic strategy for PKD. However, validating miR-17~92 as a therapeutic target requires that its role is studied in orthologous mouse models that resemble the human ADPKD phenotype of adult-onset, slowly-growing cysts. HYPOTHESIS: Increased levels of miR-17~92 promote cyst growth in ADPKD by reducing the dosage of multiple gene products in the cystic pathway.
AIMS : We will use complementary genetic and pharmaceutical approaches to determine whether inhibition of miR-17~92 retards cyst growth and increases the expression of target cystic kidney disease genes in orthologous models of ADPKD. To provide relevance to human disease, we will determine whether miR- 17~92 is up-regulated and the target cystic kidney disease genes are downregulated in human ADPKD samples. Finally, we will determine whether miR-17-mediated inhibition of Pkd1 and Pkd2 is sufficient and necessary to promote cyst growth in vivo.
ADPKD is a common but incurable genetic disease. The proposed studies may show for the first time that inhibiting microRNAs is a novel therapeutic strategy for ADPKD. These studies will also be the first to test the feasibility of antimirs as therapeutic agents in ADPKD.
