One healthy copy of a faulty gene can stop the formation of harmful cysts, which occur gradually in polycystic kidney disease (PKD), according to research. This suggests that it’s possible for researchers to develop a customized gene therapy in the future to treat the illness.

They also found that a particular class of medication called a glycoside can circumvent the consequences of the faulty gene in Parkinson’s disease. The findings may pave the way for novel therapy strategies to address PKD, which affects millions of people globally. The work was published in Cell Stem Cell(link is external) and was partially supported by the National Institutes of Health (NIH).

Researchers investigated the genetics of PKD, a potentially fatal hereditary kidney disease in which a gene deficiency causes small kidney tubes to swell like water balloons and create cysts over decades, using gene editing and 3-D human cell models known as organoids.

Kidney failure and impaired renal function may result from the cysts’ encroachment on healthy tissue. One healthy gene copy and one faulty gene copy are present in the cells of the majority of PKD patients from birth.

“Human PKD has been so difficult to study because cysts take years and decades to form,” University of Washington in Seattle senior study author Benjamin Freedman, Ph.D., stated. “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.”

Freedman and his colleagues wanted to know if 3-D human mini-kidney organoids with one normal gene copy and one defective copy would generate cysts in order to gain a better understanding of the genetic reasons cysts form in PKD. From induced pluripotent stem cells, which can differentiate into any type of cell in the body, they created organoids, which can replicate the form and functions of an organ.

The researchers employed a gene editing method called base editing to introduce mutations in specific regions of the PKD1 and PKD2 genes in human stem cells in order to produce organoids with alterations that were clinically significant. They concentrated on four different kinds of mutations in these genes that are known to impair the synthesis of polycystin protein, which is how PKD is caused. The most severe variants of Parkinson’s disease are linked to disruptions in polycystin-1 and polycystin-2, two different protein types.

Next, they contrasted cells in organoids that had two gene copy mutations with those that had just one gene copy mutation. In certain instances, they also employed gene editing to fix mutations in one of the two copies of the gene to observe the impact on cyst development. It was discovered that organoids bearing two faulty gene copies consistently developed cysts, while those with one faulty and one good gene copy did not develop 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,” according to Freedman. “It’s unclear what such a trigger would look like, and until now, we haven’t had a good experimental model for human PKD.”

Freedman stated that even though the cells with one healthy gene copy only produce half of the typical amounts of polycystin-1 or polycystin-2, that was still enough to stop cysts from growing. He went on to say that the findings point to the necessity of a second trigger and that the disease may be prevented by averting the second strike.

Additionally, the organoid models provide the first chance to examine the impact of a family of medications called eukaryotic ribosomal selective glycosides on the production of PKD cysts.

Additionally, the organoid models provide the first chance to examine the impact of a family of medications called eukaryotic ribosomal selective glycosides on the production of PKD cysts.

“These compounds will only work on single base pair mutations, which are commonly seen in PKD patients,” Freedman clarified. “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.”

The medications, according to Freedman’s team, could increase the levels of polycystin-1 to 50% and stop cysts from forming by restoring the ability of genes to produce polycystin. Adding the medications inhibited the growth of the cysts even after they had formed.

Freedman proposed that testing individuals with currently available glycoside medications would be the next step. Researchers might also look into treating Parkinson’s disease (PKD) via gene therapy.