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Scientists use mini-kidney models to identify possible cures for polycystic kidney disease – ScienceDaily

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In a new study by Cellular stem cellscientists in Andy McMahon’s USC lab created simple kidney-like structures called organoids and used them to identify potential drugs to treat polycystic kidney disease in adults.

Affecting 8 million patients worldwide, the adult-onset form of polycystic kidney disease follows a so-called “autosomal dominant” pattern of inheritance – meaning the disease develops when a person inherits a bad copy of the gene PKD1 or PKD2, and the activity of the second healthy copy is also lost. Autosomal dominant polycystic kidney disease (ADPKD) causes large, fluid-filled cysts in many regions of the kidney, leading to loss of kidney function and other life-threatening complications that affect the liver, pancreas, and heart. Talvaptan, the only FDA-approved drug to treat ADPKD, slows but does not block the progression of the disease and works only on a group of cysts made up of a specific type of kidney cell.

To accelerate the search for new treatments for ADPKD, first authors Tracy Tran, Cheng (Jack) Song, and colleagues started with human pluripotent stem cells, which have the ability to either multiply to produce more stem cells or differentiate into different cell types. specialized cells. They used these pluripotent stem cells to grow organoids, which consist of one or two structures that resemble the filtering units of the kidney, known as nephrons.

“These organoids are simple, reproducible, scalable and cost-effective,” said Professor McMahon, lead author of the study, chair of the Division of Stem Cell Biology and Regenerative Medicine and director of the Eli and Edith Broad Center for Regenerative Medicine Medicine and Stem Cell Research at USC. “Most importantly, the organelles can consistently recapitulate key aspects of normal human kidney development as well as cyst formation in ADPKD.”

The scientists demonstrated that the organoids contain many of the cellular progenitors and genetic signatures needed to build the kidneys during embryonic development. When implanted into a mouse, the nephron-like structures of the organoids began to develop a vascular network and even achieved a limited ability to filter waste – one of the most important functions of the kidneys.

To make organoids useful for studying ADPKD, the scientists used CRISPR/Cas9 gene editing to inactivate PKD1 or PKD2. As expected, the gene-edited organoids began to form cysts, which eventually separated and grew to centimeters in diameter.

The scientists then performed the first screen using gene-edited human organelles to identify potential therapeutics for ADPKD, focusing on a collection of enzyme inhibitors to provide broad insight into the cellular mechanisms that control cyst formation.

“Our organoids have proven to be very useful for identifying candidate therapeutics that deserve further study for the treatment of ADPKD,” said Song, who is an Amgen postdoctoral fellow in the McMahon lab.

After testing a collection of 247 enzyme-inhibiting compounds on organoids, the scientists found nine that inhibited cyst growth without halting overall organoid growth. 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 ultimately providing transplants to replace functioning organs in patients,” said Tran, who performed the research as a postdoctoral fellow at McMahon. Labs, and is currently a postdoctoral fellow at UCLA.

Additional co-authors are Trang Nguyen, Shun-Yang Cheng, Jill A. McMahon, Rui Yang, Qu Guo, Balint Der and Nils O. Lindström of USC, and Daniel S.-H. Lynn at Amgen. Guo is currently completing his graduate studies at UCLA, while Lin works at 23andMe.

This work was supported entirely by federal funding from the National Institute of Diabetes and Digestive and Kidney Diseases (grant DK054364) and the National Institutes of Health (training grant T32HD060549). Additional support came from private sources, including the Amgen-USC Graduate Fellowship Program and generous donations that established the Choi Family Center for Therapeutic Screening at USC.

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