Researchers from Andy McMahon’s USC lab used organoids, which are simple kidney-like structures, in a recent study that was published in the journal Cell Stem Cell to identify potential treatments for adult-onset polycystic kidney disease.
The “autosomal dominant” pattern of inheritance for the adult-onset form of polycystic kidney disease, which affects 8 million people worldwide, indicates that the disease develops when a person acquires a defective copy of the PKD1 or PKD2 gene and the function of the second healthy copy also vanishes.
Autosomal dominant polycystic kidney disease (ADPKD), which also poses a serious risk to the liver, pancreas, and heart, causes large fluid-filled cysts to grow in numerous kidney regions.
Tolvaptan is the only FDA-approved medication for ADPKD, and it is only effective in a subset of kidney cell-based cysts. The progression of the disease is slowed, but not stopped.
First authors Tracy Tran, Cheng (Jack) Song, and their colleagues started with human pluripotent stem cells, which can either multiply to produce more stem cells or develop into a variety of specialized cells, to quicken the search for new treatments for ADPKD.
Organoids with one or more nephron-like structures—the filtering cells of the kidney—were made using these pluripotent stem cells.
“These organoids are simple, reproducible, scalable, and cost-effective,” Professor McMahon, the lead author, said.
Most importantly, organoids can accurately mimic both cyst formation in ADPKD and key aspects of normal human kidney development, says the lead author.
Scientists demonstrated that the organoids contained many of the genetic markers and cell precursors required for the development of a kidney in an embryo.
When the organoids were implanted into a mouse, the structures that resembled nephrons began to develop blood vessels and even had a limited capacity to filter wastes, one of the kidney’s most crucial functions.
To make the organoids useful for studying ADPKD, the researchers used CRISPR/Cas9 gene editing to inactivate PKD1 or PKD2. The expected development of cysts in the gene-edited organoids led to their eventual separation and expansion to centimeter-sized cysts.
In order to gain a thorough understanding of the cellular mechanisms controlling cyst formation, the researchers focused on a group of enzyme inhibitors when conducting the initial screening to identify potential treatment agents for ADPKD using gene-edited human organoids.
“Our organoids proved to be very useful for identifying therapeutic drug candidates that merit further study for the treatment of ADPKD,” says Song, a postdoctoral Amgen Scholar in the McMahon Lab.
Researchers discovered 9 compounds that successfully slowed cyst growth without impairing organoid development after subjecting organoids to 247 different enzyme inhibitors. Quinazoline was one substance that worked particularly well.
Organoids will eventually be used to replace patients’ missing organ function through transplants, according to Tran. “Organoids will become an increasingly powerful tool for modeling and understanding human disease, identifying potential treatments, and providing transplants,” she continued.
