Blocking the inhibition of PKD1 and PKD2 gene expression by deleting a binding site for microRNAs hindered the formation and growth of kidney cysts in autosomal dominant polycystic kidney disease (ADPKD) models, UT Southwestern researchers reported. The findings, published in Nature Communications, suggest a method for gene therapy with the potential to arrest or cure ADPKD.

For greater than 25 years, we’ve got known that ADPKD is attributable to mutations of PKD1 or PKD2 genes. Yet, no therapeutic strategy exists to go after these root causes.”

Vishal Patel, M.D., Associate Professor of Internal Medicine, Division of Nephrology at UTSW and corresponding writer of the paper

ADPKD is amongst essentially the most common human genetic conditions and essentially the most frequent genetic explanation for kidney failure, affecting an estimated 12.5 million people worldwide. ADPKD is an inherited disease through which patients typically inherit one mutated copy of PKD1 (or PKD2) and one normal copy. The disease is characterised by the frequent formation of many small fluid-filled sacs called kidney cysts, that are believed to form when the degrees of PKD1 or PKD2 fall below a critical threshold. This could occur when the traditional copy of the gene doesn’t produce enough of the proteins Polycystin-1/Polycystin-2.

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

PKD1 accommodates a binding site for miR-17, a microRNA that is very expressed and lively in models of ADPKD. So, Dr. Patel and his colleagues asked if blocking the binding of miR-17 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 stability of the mRNA strand, raised Polycystin-1 levels, and decreased kidney cyst growth. Furthermore, 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 might be a promising goal for polycystic kidney disease (PKD) treatment.

“There are many genetic conditions where one copy of the causative gene is mutated, but the opposite copy remains to be normal. Our approach to harnessing the remaining normal copy is probably going applicable to many other diseases besides PKD,” said Dr. Patel.

UT Southwestern opened a PKD and genetic kidney disease clinic in 2016 that’s co-led by Ronak Lakhia, M.D., Assistant Professor of Internal Medicine within the Division of Nephrology at UTSW. Dr. Lakhia is the co-first writer on this study with Harini Ramalingam, Ph.D., a postdoctoral researcher within the Patel lab. The UTSW PKD clinic is now the biggest such clinic in Texas, said Dr. Lakhia, gaining recognition as a site for progressive 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 has patents involving anti-miR-17 for the treatment of ADPKD and serves as a scientific consultant for Regulus Therapeutics and other firms as disclosed within the paper.

Source:

UT Southwestern Medical Center

Journal reference:

Lakhia, R., et al. (2022) PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression. Nature Communications. doi.org/10.1038/s41467-022-32543-2.