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Most people with PKD are born with one healthy gene copy and one defective gene copy in their cells.

Organoids Help Uncover the Genetics of Kidney Disease

Innovative disease modeling and gene editing techniques begin to answer long-standing questions

National Institutes of Health
Published:Apr 05, 2024
|3 min read
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Researchers have shown that dangerous cysts, which form over time in polycystic kidney disease (PKD), can be prevented by providing a single, normal copy of the causative gene. This means there is potential to design a gene therapy to treat the disease. Researchers also discovered that a type of drug, known as a glycoside, can sidestep the effects of the defective gene in PKD. The discoveries could set the stage for new therapeutic approaches to treating PKD, which affects millions worldwide. The study, partially funded by the National Institutes of Health (NIH), is published in Cell Stem Cell.

What causes polycystic kidney disease?

Scientists used gene editing and 3D human cell models, known as organoids, to study the genetics of PKD, a life-threatening, inherited kidney disorder, in which a gene defect causes the formation of cysts over decades. The cysts can crowd out healthy tissue, leading to kidney function problems and kidney failure. Most people with PKD are born with one healthy gene copy and one defective gene copy in their cells.

“Human PKD has been so difficult to study because cysts take years and decades to form,” said senior study author Benjamin Freedman, PhD, at the University of Washington, Seattle, WA. “This new platform finally gives us a model to study the genetics of the disease and hopefully start to provide answers to the millions affected by this disease.”

To better understand the genetic reasons cysts form in PKD, Freedman and his colleagues sought to determine if the kidney organoids with one normal gene copy and one defective copy would form cysts. 

How gene copies affect the etiology of PKD

The researchers grew organoids, which can mimic the functions and features of an organ, from induced pluripotent stem cells. They used base editing to create clinically relevant mutations in certain locations on the PKD1 and PKD2 genes in human stem cells. They focused on four types of mutations in these genes that are known to cause PKD by disrupting the production of polycystin protein. Disruptions in two types of the protein—polycystin-1 and polycystin-2—are associated with the most severe forms of PKD.

They then compared cells with two gene copy mutations in organoids to cells with only one gene copy mutation. In some cases, they also used gene editing to correct mutations in one of the two gene copies to see how this affected cyst formation. They found organoids with two defective gene copies always produced cysts and those that carried one good gene copy and one bad copy did not form cysts. 

“We didn’t know if having a gene mutation in only one gene copy is enough to cause PKD, or if a second factor, such as another mutation or acute kidney injury was necessary,” Freedman said. “It’s unclear what such a trigger would look like, and until now, we haven’t had a good experimental model for human PKD.”

According to Freedman, the cells with one healthy gene copy make only half the normal amount of polycystin-1 or polycystin-2, but that was sufficient to prevent cysts from developing. He added that the results suggest the need for a second trigger and that preventing that second hit might be able to prevent the disease.

Organoids as models for drug testing

The organoids also provided the first opportunity to study the effectiveness of a class of drugs known as eukaryotic ribosomal selective glycosides on PKD cyst formation. “These compounds will only work on single base pair mutations, which are commonly seen in PKD patients,” explained Freedman. “They wouldn’t be expected to work on any mouse models and didn’t work in our previous organoid models of PKD. We needed to create that type of mutation in an experimental model to test the drugs.”

Freedman’s team found that the drugs could restore the ability of genes to make polycystin, increasing the levels of polycystin-1 to 50 percent and preventing cysts from forming. Even after cysts had formed, adding the drugs slowed their growth. Freedman suggested that the next step would be to test existing glycoside drugs in patients. Researchers also could explore using gene therapy to treat PKD.

- This press release was originally published on the National Institutes of Health website