UT Southwestern researchers have partnered with a California biotechnology firm to develop a potential drug to treat autosomal dominant polycystic kidney disease, an incurable genetic disease that often leads to end-stage kidney failure.
The drug treatment, called RGLS4326, is currently in preclinical animal testing at Regulus Therapeutics in San Diego, Calif. Once complete, a human clinical trial will take place later this year.
According to Dr. Vishal Patel, assistant professor of internal medicine at UT Southwestern who is senior author of a study describing research leading to the drug’s development, polycystic kidney disease “causes numerous fluid-filled cysts to form in the kidney” and “sometimes grows to the size of a football.” Eventually, these cysts interfere with the kidney’s ability to filter blood and remove bodily waste, leading to a 50 percent chance of kidney failure by age 60.
Research for treatment began in 2009, after Patel looked for tiny RNA fragments that affect normal gene expression, called microRNAs, that might underlie progression of ADPKD.
“Because microRNAs are so small, drugs can easily be designed against them,” Patel said in a statement. “And since we know the [genetic] sequence of every known microRNA, all that is required is to prepare an anti-microRNA with a sequence that is exactly the opposite of the microRNAs.”
In this study, Patel and researchers found a microRNA cluster, 17~92, indeed appeared to promote kidney cyst growth.
After conducting experiments on four models, the team found the test drug (centered around findings from the microRNA cluster) slowed the growth of kidney cysts in two models and in cell cultures of human kidney cysts.
In 2013, Dr. Patel and fellow researchers reported in Proceedings of the National Academy of Sciences that this microRNA cluster indeed appeared to promote kidney cyst growth. These findings were published in 2013 in Proceedings of the National Academy of Sciences, and later used a catalyst to develop the drug to potentially cure ADPKD.
Using four mouse models, the team next studied whether inhibiting microRNA would slow cyst growth and delay ADPKD progression. According to UT Southwestern, the group found “genetically deleting microRNA-17~92 slowed cyst growth and more than doubled the life spans 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, the study showed.
Funding was provided by the National Institutes of Health and the PKD Foundation. UT Southwestern and Regulus Therapeutics have applied for a patent for treatment of polycystic kidney disease with the specific microRNA inhibitors.