Polycystic in vitro

Kidney organoids will help in the search for a cure for polycystic

Elina Stoyanova, PCR.news

Eight million people worldwide suffer from polycystic kidney disease. In approximately 93% of cases, autosomal dominant polycystic kidney disease (ADPP) is associated with mutations in the PKD1 and PKD2 genes. The main approaches to therapy are dialysis and transplantation. In this regard, the search for drugs that can slow down or stop the process of formation and growth of cysts is especially relevant. To date, there is only one drug on the market that slows down the growth of cysts in some patients — tolvaptan.

Kidney organoids are grown on the basis of pluripotent stem cells. The resulting model organ contains several types of nephron cells. The process of growing such organoids is expensive and difficult to reproduce. An international group of scientists has presented a new platform for obtaining renal organoids, modeling ADP and searching for new therapeutic drugs.

For large-scale and cost-effective production, the researchers grew organoids on EZSPHERE tablets. On one tablet, they received up to 400 aggregates with 1500 cells in each. During the immune analysis of cells and the study of expression profiles, the researchers were convinced that the grown organoids function like kidneys.

Kidney organoids

Scientists have grown homogeneous nephron-like structures. To confirm the uniformity of organoids in different cells, they performed quantitative PCR. The functioning of the structures was studied by sequencing the RNA of single cells. The researchers also showed that the resulting cells are similar to kidney cells in the early stages of development. To do this, they compared the cells obtained in vitro with the cells taken from the embryo at the 17th week of development. When transplanted to mice, the authors demonstrated that organoids induce the formation of blood vessels, and are also limited in their ability to filter out dextran.

Next, scientists using the CRISPR-Cas9 system made changes to the PKD1 and PKD2 genes. Inactivation of genes led to the appearance of cysts. The researchers screened a library of annotated low molecular weight protein kinase inhibitors to identify drugs that inhibit the growth of cysts. In total, the scientists tested 247 inhibitors, nine of them had a therapeutic effect. Quinazoline was particularly effective.

Article by Tran et al. A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery is published in the journal Cell Stem Cell.

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