Polycystic kidney disease (PKD) is an inherited, and currently incurable, disorder that affects more than 600,000 people in the United States. The disease causes fluid-filled cysts which can impair kidney function and lead to kidney failure, an outcome requiring dialysis or transplant.
However, even patients who are fortunate enough to receive a new kidney may be vulnerable to other health challenges associated with PKD. Harmful cysts can grow on the liver and pancreas and the disease can contribute to high blood pressure and vascular complications.
Because PKD is a whole-body disease, scientists are looking for whole-body treatments. One known target is the mTOR pathway, which regulates many aspects of cell biology and controls important processes related to metabolism and immunity. Overactivity of mTOR can lead to disorders of cell proliferation, like cancer.
“It’s really a growth pathway,” says Dr. Benjamin Freedman, an associate professor of Medicine/Nephrology and a member of the Institute for Stem Cell and Regenerative Medicine (ISCRM). “When you see mTOR activity in a cell, it means the cells are growing and dividing. That’s why it’s a target for cancer treatment. And that’s why we think it could be a target for PKD treatment.”
It’s more than a hunch. Freedman and his team have observed elevated mTOR in their PKD research. And mTOR inhibitors, like the drugs rapamycin (sirolimus) and everolimus, have been shown to slow cyst growth in mouse models, but have been less effective at safe doses in humans.
The question for the field is whether new generations of mTOR inhibitors might be safe and effective in humans. While it is too soon for human clinical trials, it is possible to test potential therapeutics in the human induced pluripotent stem cell-derived PKD organoids that the Freedman Lab has been using to study the disease for years.
Now, new research published in Stem Cell Reports suggests that a novel rapamycin analog known as AV457, which was developed by Aeovian Pharmaceuticals (Berkeley, CA) to reduce side effects of mTOR suppression, may be safer at higher doses, and therefore more potent against cysts, than everolimus. Freedman is the senior author of the paper. The first author is Ramila Gulieva, a Research Scientist in the Freedman Lab.
The results seem to be attributed at least in part to the dual structure of mTOR, which is made up of two complexes, mTORC1 and mTORC2. Freedman explains that mTORC1 is the stronger driver of PKD cyst growth; mTORC2, on the other hand, is tasked with regulating inflammatory and metabolic functions. Because the new molecule was designed to specifically target mTORC1, there was reason to believe it would outperform everolimus in this case.
Freedman speaks to the findings. “What we saw was encouraging. In terms of efficacy, the AV457 molecule was essentially tied with everolimus. But crucially, it had fewer negative effects. This indicates there is a way to get a high level of systematic mTOR blockage that would only target unwanted growth.”
Key questions remain about the relationship between mTOR and PKD. For example, is it an abnormality with mTOR that causes cysts to arise – or are cysts developing for other reasons and mTOR is feeding their spread as a growth pathway? Freedman says that is a topic worthy of further investigation.
“Our research supports this role for mTOR in PKD and points to mTOR as a target for treatment. Fundamentally, though, we need to know more about the molecular pathway of PKD. We know the genes that cause the disease. We know they interact with the mTOR pathway. But we need to grasp the root of the problem. We need to understand more about what’s happening upstream and downstream along this pathway.”
Still, Freedman is optimistic about the translational implications of the recent discovery. “Ultimately, we hope to help bring an effective therapy to market. The goal would be to have a treatment for PKD that works consistently, that can be broadly applied, and that doesn’t have side effects that would be limiting for millions of people. And we believe this study is another big step in that direction.”
Acknowledgements
The work was supported by a research grant from Aeovian Pharmaceuticals (B.S.F.); NIH awards R01DK117914 (B.S.F.), U2CTR004867 (B.S.F.), R41DK136452 (Fu and B.S.F.), and UG3TR003288 (Himmelfarb); a Washington Research Foundation Technology Commercialization grant (B.S.F.); and the Lara Nowak Macklin Research Fund.