Polycystic Kidney Disease Pediatric Research and Clinical Trials

A new target in polycystic kidney disease

In polycystic kidney disease (PKD), fluid-filled cysts gradually take over the kidneys, causing them to fail and forcing patients to go on chronic dialysis—or wait for a kidney transplant. Hopes for a cure were raised when animal models showed promise in drugs inhibiting mTOR, a protein that coordinates cell growth and is over-active in PKD. But recent clinical trials brought disappointing results.

Probing deeper into the biology, Jordan Kreidberg, PhD, and Shan Qin, MD, PhD, in Children’s Hospital Boston’s Division of Nephrology, have opened up a new option. They found that the excess mTOR activation results from unwanted activity of a cell receptor called c-Met. Normally, after c-Met is activated, it is degraded, but in PKD, it never gets marked for degradation. When the researchers used an existing compound to block c-Met activity in mouse models, cysts were markedly fewer and smaller.

Kreidberg hopes that c-Met inhibitors, already being used in cancer trials, can eventually be tested in PKD patients. Since they are more specific in their action than mTOR inhibitors, they may be less toxic, and could potentially be combined with mTOR inhibitors and other drugs.  “PKD is quite complex, with several regulatory pathways involved,” Kreidberg says.  “It will likely benefit from sub-toxic doses of multiple agents, similar to cancer chemotherapy.” (Journal of Clinical Investigation, online September 13.)