Study identifies promising target for treatment of polycystic kidney disease

Blocking inhibition of PKD1 and PKD2 gene expression by deleting a binding site for microRNAs impaired renal cyst formation and growth in models of autosomal dominant polycystic kidney disease (ADPKD), researchers report. from UT Southwestern. The findings, published in Nature Communications, suggest a gene therapy strategy that could stop or cure ADPKD.

For more than 25 years, we have known that ADPKD is caused by mutations in the PKD1 or PKD2 genes. Yet no therapeutic strategy exists to address these root causes.”

Vishal Patel, MD, associate professor of internal medicine, division of nephrology at UTSW and corresponding author of the article

ADPKD is one of the most common human genetic diseases and the most common genetic cause of kidney failure, affecting approximately 12.5 million people worldwide. ADPKD is an inherited condition in which patients typically 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 levels of PKD1 or PKD2 fall below a critical threshold. This can happen when the normal copy of the gene does not produce enough Polycystin-1/Polycystin-2 proteins.

Proteins are produced (or translated) from the messenger ribonucleic acid (mRNA) of a gene. At one end of the mRNA strand is a region of code that helps protect it from degradation, but can also control how much protein is made. Binding of microRNAs to this region of the mRNA code can block translation, leading to the production of less protein.

PKD1 contains a binding site for miR-17, a highly expressed microRNA active in models of PKRAD. So, Dr. Patel and his colleagues asked if blocking the binding of miR-17 to PKD1 could prevent the formation of kidney cysts.

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, increased polycystin-1 levels, and decreased kidney cyst growth. Additionally, the group found that blocking miR-17 binding to PKD1 mRNA with an anti-miR-17 drug after cyst formation also decreased cyst growth, indicating that this interaction may be a promising target for the treatment of polycystic kidney disease (PKD).

“There are many genetic conditions in which one copy of the causative gene is mutated, but the other copy is still normal. Our approach to harnessing the remaining normal copy is likely applicable to many other diseases besides PKD,” said said Dr. Patel.

UT Southwestern opened a PKD and Genetic Kidney Disease Clinic in 2016, co-directed by Ronak Lakhia, MD, assistant professor of internal medicine in UTSW’s Division of Nephrology. Dr. Lakhia is the co-first author of this study with Harini Ramalingam, Ph.D., a postdoctoral researcher in the Patel laboratory. The UTSW PKD Clinic is now the largest such clinic in Texas, Dr. Lakhia said, earning recognition as a site for innovative clinical trials.

Other researchers who contributed to this study include Patricia Cobo-Stark, Laurence Biggers, Andrea Flaten and Jesus Alvarez, all of 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 holds patents involving anti-miR-17 for the treatment of ADPKD and is a scientific consultant for Regulus Therapeutics and other companies, as noted in the article.


UT Southwestern Medical Center

Journal reference:

Lakhia, R. et al. (2022) Cis-inhibition of PKD1 and PKD2 mRNAs leads to progression of polycystic kidney disease. Nature Communication.

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