An experimental drug called roscovitine may inhibit a degenerative kidney disease that so far has defied cure, a study in mice shows.
Combined with promising results from animal studies on other potential drugs, the new finding brightens the outlook for people with the inherited condition called polycystic kidney disease (PKD). The disease, whose symptoms often don’t arise until adulthood, usually causes back pain, high blood pressure, urinary tract infections, and, ultimately, kidney failure. Other than a complete-kidney transplant, available treatments address only the disease’s symptoms.
People with PKD have a mutation in one of two genes that encode proteins called polycystins. These proteins are necessary for the proper functioning of organelles called cilia that protrude from kidney cells. One hypothesis holds that cilia sense the flow and composition of fluids in the kidneys. The cilia rely on polycystins to relay this information into a cell and regulate its development and growth.
In the absence of polycystins, cilia function goes awry. Without a growth regulator, enzymes called kinases become overactive and cause the kidney cells to proliferate abnormally and to secrete fluids when they should be absorbing them, says study coauthor Oxana Ibraghimov-Beskrovnaya, a cell biologist at Genzyme Corp. in Framingham, Mass. The resulting cysts, as they accumulate, sabotage the kidneys’ ability to remove impurities from the blood.
Roscovitine inhibits some of the kinases that play a role in PKD. Researchers injected the drug or an inert substance into mice that had been genetically engineered to develop kidney cysts. After several weeks, the roscovitine-treated animals’ kidneys weighed less and were smaller than those in the untreated mice.
That suggests the drug shrank the animals’ cysts, says Ibraghimov-Beskrovnaya. The kidneys in the treated mice also filtered blood more effectively than kidneys in the control mice did, the researchers report online and in the Dec. 14 Nature.
While roscovitine shows promise, it won’t be tested in people with PKD for at least a year, says study coauthor Katherine W. Klinger, a geneticist at Genzyme.
Meanwhile, several other drugs, including rapamycin, octreotide, and tolvaptan, that succeeded in animal tests for PKD are now being tested in people.
“The speed of discovery in the field is better than it’s ever been,” says nephrologist Vicente E. Torres of the Mayo Clinic in Rochester, Minn., whose team has investigated tolvaptan.
“These drugs act at different points along a chain of abnormalities that we believe occurs in PKD,” he says. “The more drugs we have at different steps, the better, [because] they create opportunities in the future for using combinations.”