UT Southwestern researchers report that inhibition of PKD1 and PKD2 gene expression by deleting a binding site for microRNAs impeded the formation and growth of kidney cysts in models of autosomal dominant polycystic kidney disease (ADPKD). The findings, published in Nature Communications, point to a gene therapy strategy with the potential to stop or treat ADPKD.
For more than 25 years, we have known that ADPKD is caused by mutations in the PKD1 or PKD2 genes. However, there is no therapeutic strategy to follow up on these root causes.”
Vishal Patel, MD, associate professor of internal medicine, division of nephrology at UTSW and corresponding author of the paper
ADPKD is the most common human genetic condition and the most common genetic cause of kidney failure, affecting an estimated 12.5 million people worldwide. ADPKD is a genetic disease in which patients usually inherit one mutated copy of PKD1 (or PKD2) and one normal copy. The disease is characterized by the frequent formation of many small fluid-filled sacs called kidney cysts, which are thought to form when PKD1 or PKD2 levels fall below a critical threshold. This can happen when the normal version of the gene does not produce enough Polycystin-1/Polycystin-2 proteins.
Proteins are produced (or translated) from the gene’s messenger ribonucleic acid (mRNA). At one end of the mRNA strand is a region of the codon that helps protect it from degradation but can also control the amount of protein that is produced. The binding of the microRNA to this region of the mRNA codon can inhibit translation, resulting in less protein production.
PKD1 contains a binding site for miR-17, a microRNA that is highly expressed and active in ADPKD models. Therefore, Dr. Patel and colleagues wondered if blocking miR-17 binding to PKD1 could prevent kidney cyst formation.
The researchers deleted the miR-17-binding site from PKD1 mRNA in cell cultures and an ADPKD mouse model. Their results indicated that deletion of the binding site increased mRNA strand stability, raised polycysteine-1 levels, and decreased kidney cyst growth. Moreover, the group found that blocking miR-17 binding to PKD1 mRNA using an anti-miR-17 drug after cyst formation also reduced cyst growth, indicating that this interaction could be a promising target for the treatment of polycystic kidney disease (PKD). ).
“There are many genetic conditions where one copy of the causative gene is mutated, but the other copy remains normal. Our approach to harnessing the residual normal copy is likely to be applicable to many other diseases besides PKD,” said Dr. Patel.
UT Southwestern opened a clinic for PKD and hereditary kidney disease in 2016 that was co-led by Ronak Lakhia, MD, assistant professor of internal medicine in the division of nephrology at UTSW. Dr. Lakhia is the co-first author of this study with Harini Ramalingam, PhD, a postdoctoral researcher in Patel’s lab. Now the largest clinic of its kind in Texas, Dr. Lajea said UTSW PKD has gained a reputation as a site for innovative clinical trials.
Other researchers who contributed to this study included Patricia Cobo-Stark, Lawrence Biggers, Andrea Flatten and Jesus Alvarez, all from UTSW. and Chun-Mien Chang, Tania Valencia, Darren P. Wallace, and Edmund C. Lee.
This work was supported by grants from the National Institutes of Health (R01DK102572) and the Department of Defense (D01 W81XWH1810673). Dr. Patel owns patents related to the miR-17 antagonist for the treatment of ADPKD and serves as a scientific advisor to Regulus Therapeutics and other companies as outlined in the paper.