Autosomal dominant polycystic kidney disease (ADPKD) accounts for up to 10% of end-stage kidney disease, which is when then the kidneys fail. The only cure is kidney transplantation, but drugs can delay the progression of the disease. A key factor in ADPKD is the formation of cysts, which gradually accumulate and lead to the kidney failure. CiRA researchers report in a new study organoid technology using human iPS cell technology that can be used to model the cyst formation and find drugs to prevent it.

To study ADPKD, scientists have many models to choose from, including organoid models, but according to CiRA Professor Kenji Osafune, these models do not apply to the majority of patients.

"Organoids with homozygous mutations have already been reported, but these models do not apply to 85% of ADPKD patients who have heterozygous mutations in PDK1. Little is known about cAMP levels in the kidney and cystogenesis," he said.

PDK1 is the gene most frequently mutated in ADPDK patients. Osafune's research team prepared iPS cells with heterozygous mutations in the gene two ways. First, they reprogrammed cells from ADPKD patients with heterozygous gene mutations. The other was to use CRIPSR-Cas9 gene editing technology to generate mutations in the gene from iPS cells made from healthy donors.

Interestingly, using a standard protocol, the organoids formed by these iPS cells did not show abnormal cysts. However, adding a cAMP stimulant to protocol triggered cyst formation. This same effect was seen in organoids made from iPS cells without the PDK1 mutation, but to a much lesser degree.

"Forskolin causes cyst formation. We wanted to compare the different effect between organoids with the mutation and those without," said Osafune.

Finding similar cyst patterns between the gene edited and patient organoids, the study goes on to show that patient organoids could make for a promising tool in drug discovery by showing how the organoids respond to drugs currently used in the clinic or developed against ADPKD.

"Patient iPS cells may have advantages over gene-edited ones in drug discovery for ADPKD because they represent the pre-symptomatic state and have the potential to develop bona fide renal cysts", Osafune said.

• doi: 10.1016/j.bbrc.2020.06.141