Mini kidney models to identify potential drugs for polycystic kidney disease

USA: In a new study in Cell Stem Cell, scientists from the USC laboratory have generated simple kidney-like structures called organoids and used them to identify potential drugs to treat adult-onset polycystic kidney disease.

Polycystic kidney disease, presents an "autosomal dominant" pattern of inheritance meaning that the disease develops when a person inherits a bad copy of the gene PKD1 or PKD2, and the activity of the second good copy is also lost.

Autosomal dominant polycystic kidney disease (ADPKD) causes large fluid-filled cysts in many regions of the kidney, leading to the loss of kidney function and other life-threatening complications affecting the liver, pancreas, and heart. Tolvaptan, the only FDA approved drug to treat Autosomal dominant polycystic kidney disease, slows but does not block disease progression, and only works in a subset of cysts composed of a particular kidney cell type.

The scientists demonstrated that the organoids contained many of the cellular precursors and genetic signatures required to build the kidney during embryonic development. When implanted into a mouse, the organoids' nephron-like structures started to develop vasculature and even attained a limited capacity to filter wastes, one of the most important functions of the kidney.

To make the organoids useful for studying Autosomal dominant polycystic kidney disease, the scientists used CRISPR/Cas9 gene editing to inactivate PKD1 or PKD2. As anticipated, the gene-edited organoids began to form cysts, which eventually detached and grew to centimeters in diameter.

The scientists then performed the first screen using gene-edited human organoids to identify potential therapeutic drugs for ADPKD, focusing on a collection of enzyme inhibitors to give a broad insight into the cellular mechanisms controlling cyst formation.

After testing a collection of 247 enzyme inhibitor compounds on the organoids, the scientists found nine that inhibited the growth of the cysts, without stunting the overall growth of the organoids. One compound, quinazoline, was particularly effective.

"In the future, organoids will become an increasingly powerful tool for modeling and understanding human disease, identifying potential treatments, and eventually, providing transplants to replace organ function for patients concluded the researchers.

Reference: Tracy Tran, Cheng Jack Song, Trang Nguyen,Nils O. Lindström, Daniel C.-H. Lin,Andrew P. McMahon; DOI:https://doi.org/10.1016/j.stem.2022.06.005