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January 25, 2024 — Autosomal dominant polycystic kidney disease (ADPKD), affecting more than 12 million people globally, may find a potential treatment in a compound originally developed as a cancer treatment. Researchers from MIT and Yale University School of Medicine have discovered that this compound, known as 11beta-dichloro, holds promise for shrinking kidney cysts and improving kidney function without harming healthy kidney cells.
ADPKD, the most common form of polycystic kidney disease, often leads to kidney enlargement and eventual loss of function, requiring dialysis or kidney transplant for many patients by their 60s. Currently, the only FDA-approved drug for ADPKD, tolvaptan, has side effects that include frequent urination and possible liver damage.
The study, published this week in the Proceedings of the National Academy of Sciences, outlines the groundbreaking findings of the research team led by Bogdan Fedeles, a research scientist at MIT’s Center for Environmental Health Sciences. The senior authors of the paper are John Essigmann, the William R. and Betsy P. Leitch Professor of Biological Engineering and Chemistry at MIT; Sorin Fedeles, executive director of the Polycystic Kidney Disease Outcomes Consortium and assistant professor (adjunct) at Yale University School of Medicine; and Stefan Somlo, the C.N.H. Long Professor of Medicine and Genetics and chief of nephrology at Yale University School of Medicine.
The study evolved from MIT’s work on potential cancer drugs, particularly compounds designed nearly 25 years ago containing a DNA-damaging agent called an aniline mustard. The compounds induce oxidative stress in cells, disrupting mitochondria function and inducing cell death in cancer cells.
Unexpectedly, the researchers found that these compounds could also exploit kidney cyst cells’ vulnerability to oxidative stress. Kidney cyst cells, like cancer cells, produce increased levels of free radicals due to oxidative stress. The 11beta compounds work by disrupting mitochondria function and depleting antioxidants, pushing cystic cells over their oxidative stress threshold and causing cell death.
Using two mouse models of ADPKD, the researchers demonstrated that 11beta-dichloro significantly reduced kidney cyst size and improved kidney function without affecting healthy kidney cells. They also synthesized a safer version, 11beta-dipropyl, which showed equal effectiveness in early-onset PKD.
The researchers believe that treatment with 11beta compounds once every few months or even once a year could delay disease progression, potentially avoiding the need for continuous therapies like tolvaptan. The results open up new possibilities for ADPKD treatment and offer hope for millions affected by this prevalent kidney disease.
