Potential treatment for fatal, incurable kidney disease being developed
Polycystic kidney disease is an incurable genetic disease that often leads to end-stage kidney failure. The name carries the weight of a potential early death sentence for those diagnosed.
Dr. Vishal Patel, Assistant Professor of Internal Medicine at UT Southwestern, hopes to one day change that grim prognosis.
“There isn’t a single drug on the U.S. market right now to treat the disease,” said Dr. Patel, senior author of a Nature Communications paper describing his group’s investigation. “Once your kidneys fail, your only option for survival is to get a transplant or start dialysis.”
In concert with a California biotech firm, his research team is currently testing a potential drug to treat the disease. Preclinical animal testing has been completed and an investigational new drug application has been filed by San Diego-based Regulus Therapeutics Inc. Early stage human clinical trials began in December 2017, Dr. Patel said.
Affecting about 600,000 people in the U.S., autosomal dominant polycystic kidney disease (ADPKD) causes numerous fluid-filled cysts to form in the kidney. An affected kidney, normally the size of a human fist, sometimes grows as large as a football. As their numbers and sizes increase, these cysts eventually interfere with the kidney’s ability to filter blood and remove bodily waste. About half of those affected with ADPKD suffer kidney failure by age 60, according to the National Kidney Foundation.
In 2009, Dr. Patel began searching for microRNAs that might underlie the progression of ADPKD. MicroRNAs – or miRs for short – are tiny RNA fragments that interfere with normal gene expression. Proof of their presence in humans was first reported in 2000. Those discoveries led to a groundswell of interest in developing drugs to treat diseases caused by microRNAs, Dr. Patel said, in part because the process can be straightforward once the problem-causing fragment is identified.
“Because miRs are so small, drugs can easily be designed against them. And since we know the nucleotide sequence of every known microRNA, all that is required is to prepare an anti-miR with a sequence that is exactly the opposite of the miR’s,” he said.
For those reasons, anti-microRNA compounds are a major focus right now in drug development. UT Southwestern’s foundational basic-science work, coupled with advanced clinical treatment, makes it the perfect testing ground for new lifesaving drugs such as the one Dr. Patel is testing.
Researchers in Dr. Patel’s lab focused on microRNA cluster 17~92 following identification of potential miR targets. They found that genetically deleting microRNA-17~92 slowed cyst growth and more than doubled the lifespans of some mice tested.
Based on that finding, Dr. Patel’s lab collaborated with Regulus Therapeutics to test an anti-microRNA-17 drug. The test drug slowed the growth of kidney cysts in two mouse models and in cell cultures of human kidney cysts. UT Southwestern and Regulus Therapeutics have since applied for a patent for treatment of polycystic kidney disease with miR-17 inhibitors.
