In autosomal dominant polycystic kidney disease (ADPKD) models, deleting a binding site for microRNAs prevented the inhibition of PKD1 and PKD2 gene expression, which in turn prevented kidney cyst development and growth. The research, which was published in Nature Communications, offers a gene therapy plan that may be able to stop or reverse ADPKD.
“We’ve known for more than 25 years that PKD1 or PKD2 gene mutations lead to ADPKD. However, there is no therapeutic approach to address these underlying causes “UTSW Associate Professor of Internal Medicine in the Division of Nephrology and corresponding author of the study, Vishal Patel, M.D.
With an estimated 12.5 million cases worldwide, ADPKD is one of the most prevalent human genetic diseases and the most common genetic contributor to kidney failure. Patients with ADPKD typically inherit one mutated copy of PKD1 (or PKD2) and one normal copy of the gene. Kidney cysts, which are thought to form when levels of PKD1 or PKD2 fall below a critical threshold, are a common feature of the disease and frequently form in large numbers. This may happen if the gene’s normal copy does not produce enough proteins. Polycystin-1/Polycystin-2.
A gene’s messenger ribonucleic acid (or translation) generates proteins (mRNA). The mRNA strand has a section of code at one end that aids in its protection from degradation and can also regulate the amount of protein that is produced. Less protein is produced when translation is blocked by microRNAs that bind to this section of the mRNA code.
The microRNA miR-17, which is highly expressed and active in models of ADPKD, has a binding site in PKD1. So, Dr. Patel and his associates questioned whether stopping miR-17 from binding to PKD1 could stop kidney cyst development.
The scientists altered the PKD1 mRNA in cell cultures and an ADPKD mouse model by deleting the miR-17 binding site. According to their findings, deleting the binding site improved mRNA strand stability, increased Polycystin-1 levels, and slowed the growth of kidney cysts. The team also discovered that inhibiting miR-17 binding to PKD1 mRNA with an anti-miR-17 drug after cyst formation reduced cyst growth, suggesting that this interaction may be a promising target for PKD treatment.
“There are many genetic disorders in which one copy of the mutated gene remains normal while the other copy is altered. In addition to PKD, many other diseases may benefit from our method of utilizing the remaining normal copy “Dr. Patel said.
In 2016, the Division of Nephrology at UT Southwestern established a PKD and genetic kidney disease clinic, which is co-led by Ronak Lakhia, M.D., an assistant professor of internal medicine. Together with Harini Ramalingam, Ph.D., a postdoctoral researcher in the Patel lab, Dr. Lakhia is the study’s co-first author. According to Dr. Lakhia, the PKD clinic at UTSW has grown to be the biggest of its kind in Texas and is becoming known as a location for cutting-edge clinical trials.
Along with Chun-Mien Chang, Tania Valencia, Darren P. Wallace, and Edmund C. Lee, this study also included Patricia Cobo-Stark, Laurence Biggers, Andrea Flaten, and Jesus Alvarez, all of UTSW.
The National Institutes of Health (R01DK102572) and the Department of Defense provided funding for this research (D01 W81XWH1810673). The paper says that Dr. Patel has patents on anti-miR-17 for treating ADPKD and that he works as a scientific consultant for Regulus Therapeutics and other companies.
