Autosomal-dominant (ADPKD) is the most common life-threatening genetic disease, and it affects over 600,000 patients in the United States. As an adult-onset disease, ADPKD is of significant military relevance because diagnoses are often made at an age after individuals are selected for military duty. No treatment is currently available to slow the disease progression, which leads to the growth of thousands of cysts in both kidneys. This commonly leads to kidney failure and the patients require kidney transplantation or life-long dialysis for survival.

Mutations in a large protein called polycystin-1 (PC1) are the cause of the majority of cases, but the function of PC1 has remained poorly understood. We have recently found that PC1 inhibits the activity of an important regulatory protein by the name of mTOR. mTOR plays a role in cell growth and proliferation. We found that mTOR is overly active in the kidneys of ADPKD patients and in mice with polycystic kidneys. Rapamycin is a very effective inhibitory drug for mTOR. We found that treatment of polycystic kidney mice with rapamycin results in a dramatic reduction of cyst sizes and in the preservation of kidney function. This strongly suggests that aberrant mTOR activation in ADPKD is critical for kidney cyst growth.

We now propose to study in detail the mechanism of how PC1 is able to suppress the activity of mTOR in normal kidneys. Using cultured kidney cells, we will investigate the interaction between PC1 and mTOR and identify additional regulatory factors. Using kidney samples from ADPKD patients and mice with polycystic kidneys, we will test why mutations in PC1 lead to mTOR activation. Finally, in preparation for a future clinical trial, we will investigate the effects of rapamycin on mice with polycystic kidneys. We will determine the minimal effective dose and test whether low-dose, chronic treatment or high-dose, intermittent treatment is superior.

These investigations are necessary to increase the chances of success of a future clinical trial. Rapamycin is already a clinically approved drug used for long-term treatment for immunosuppression in renal transplant patients. Based on our data, we are cautiously optimistic that rapamycin has promise to become the first available treatment to slow disease progression in ADPKD. Even a delay of the onset of kidney failure by a number of years would be a tremendous advance and would dramatically improve the quality of life of a large number of patients.