New drug candidate may shrink kidney cysts

Autosomal dominant polycystic kidney disease (ADPKD), the most common form of polycystic kidney disease, can lead to kidney enlargement and eventually loss of function. The disease affects more than 12 million people worldwide, and many patients end up needing dialysis or a kidney transplant before they reach their 60s.

Researchers at MIT and Yale University School of Medicine have found that a compound originally developed as a potential cancer treatment shows promise for treating PKD. The drug works by exploiting the vulnerability of kidney cyst cells to oxidative stress, a state of imbalance between harmful free radicals and beneficial antioxidants.

In a study using two mouse models of the disease, researchers found that the drug significantly reduced kidney cysts without harming healthy kidney cells.

“We really think this has the potential to impact the field and provide a different treatment paradigm for this important disease,” says Bogdan Fedeles, a research scientist and program director at the Center for Environmental Health Sciences at MIT and lead author of the study, which is featured this week in the Proceedings of the National Academy of Sciences.

John Essigmann, 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, CNH Long professor of medicine and genetics and chief of nephrology at Yale University School of Medicine, are senior authors of the paper.

Cells under stress

PKD usually progresses slowly. Often diagnosed in patients in their 30s, it generally does not cause serious impairment of kidney function until their 60s. The only drug approved by the FDA to treat the disease, tolvaptan, slows the growth of cysts but causes side effects, including frequent urination and possible liver damage.

Essigmann’s lab did not initially aim to study PKD; The new study grew out of work on potential new cancer drugs. Nearly 25 years ago, Robert Croy, a researcher at MIT, also author of the new PNAS study, designed compounds containing a DNA-damaging agent known as aniline mustard, which can induce cell death in cancer cells.

In the mid-2000s, Fedeles, then a graduate student in Essigmann’s lab, along with Essigmann and Croy, discovered that in addition to damaging DNA, these compounds also induced oxidative stress by interfering with mitochondria, organelles that generate energy for cells.

Tumor cells are already under oxidative stress due to their abnormal metabolism. When treated with these compounds, called 11beta compounds, the additional disruption helps kill the cells. In a study published in 2011, Fedeles reported that treatment with 11beta compounds significantly suppressed the growth of implanted prostate tumors in mice.

A conversation with his brother, Sorin Fedeles, who studies polycystic kidney disease, led the two men to hypothesize that these compounds might also be good candidates for treating kidney cysts. At the time, research into PKD was beginning to suggest that cells in kidney cysts were also experiencing oxidative stress, due to abnormal metabolism that resembles that of cancer cells.

“We were talking about a mechanism for what would be a good drug for polycystic kidney disease, and we had a hunch that the compounds I was working with could actually have an impact on ADPKD,” says Bogdan Fedeles.

11beta compounds work by disrupting the ability of mitochondria to generate ATP (the molecules that cells use to store energy), as well as a cofactor called NADPH, which can act as an antioxidant to help cells neutralize harmful free radicals. Tumor cells and kidney cyst cells tend to produce increased levels of free radicals due to the oxidative stress they are subjected to. When these cells are treated with 11beta compounds, additional oxidative stress, including additional NADPH depletion, pushes the cells over the edge.

“A little oxidative stress is acceptable, but cyst cells have a low tolerance threshold. While normal cells survive the treatment, cyst cells will die because they exceed the threshold,” explains Essigmann.

Shrinking cysts

Using two different mouse models of ADPKD, researchers showed that 11beta-dichloro could significantly reduce the size of kidney cysts and improve kidney function.

The researchers also synthesized a “defanged” version of the compound called 11beta-dipropyl, which does not include any direct DNA-damaging abilities and could potentially be safer for use in humans. They tested this compound in the early PKD model and found that it was as effective as 11beta-dichloro.

In all experiments, healthy kidney cells did not appear to be affected by the treatment. Indeed, healthy cells are able to resist a slight increase in oxidative stress, unlike diseased cells, which are very sensitive to any new disturbance, the researchers explain. In addition to restoring kidney function, the treatment also improved other clinical features of ADPKD; biomarkers of tissue inflammation and fibrosis were decreased in treated mice compared to control animals.

The results also suggest that in patients, treatment with 11beta compounds once every few months, or even once a year, could significantly delay disease progression and thus avoid the need for ongoing and expensive antiproliferative treatments such as tolvaptan.

“Based on what we know about the cyst growth paradigm, you could theoretically treat patients pulsatilely – once a year, or perhaps even less often – and have a significant impact on the total volume and kidney function,” explains Sorin Fedeles. .

The researchers now hope to carry out further tests on 11beta-dipropyl and develop ways to produce it on a larger scale. They also plan to explore related compounds that could be good drug candidates for PKD.

This story is republished courtesy of MIT News (web.mit.edu/newsoffice/), a popular site that covers news about MIT research, innovation and education.