ANIMAL tests have raised hopes of finding an effective drug treatment for polycystic kidney disease, one of the most common inherited disorders worldwide.
PKD affects around 1 in 500 people. Mutations in genes for polycystin proteins cause epithelial cells to proliferate in the kidneys, forming fluid-filled cysts. The kidneys gradually enlarge, and can eventually fail altogether. Doctors can only treat the symptoms.
Although PKD is far more common than other genetic diseases such as cystic fibrosis, it has received little research attention. But in the past few years, scientists have begun to understand its molecular mechanism. Recent studies suggest the cell proliferation is triggered by a rise in levels of the signalling molecule cyclic AMP in cells. If so, drugs that block the vasopressin V2 receptor that responds to cyclic AMP should slow the progress of the disease.
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A team led by Vicente Torres at the Mayo Clinic College of Medicine in Minnesota has now shown that a drug known as OPC31260, which targets the V2 receptor, can indeed slow cyst formation in mice with the dominant form of the disease (Nature Medicine, DOI: 10.1038/nm1004). Previous work by Torres and others has shown it protects mice against the rarer recessive form of the disease.
The fact that the approach works in mice with different forms of the disease is promising, says Richard Sandford of the University of Cambridge, who studies polycystin genes. Often a drug that works in one kind of animal model fails in another.
Torres stresses the need for human trials, but is optimistic about the prospects. 鈥淲e would hope it slows down the disease enough that it becomes irrelevant.鈥� And because the V2 receptor is found almost exclusively in kidney epithelial cells, drugs like OPC31260 should have few side effects.
A modified form of the drug, called OPC41061, has already passed safety tests and is now in advanced human trials for the treatment of congestive heart failure and cirrhosis. If the drug is approved for these diseases, it could be approved for PKD treatment more quickly. 鈥淭here鈥檚 an immediacy about this,鈥� says Sandford. 鈥淚t鈥檚 tantalisingly close.鈥�
In the past, researchers testing treatments for PKD have been plagued by the fact that the disease develops slowly over many years. 鈥淚t has been phenomenally difficult to know if you are making a difference,鈥� Sandford says. But a five-year study under way in the US has shown that scans measuring kidney volume reveal the disease鈥檚 progress, so it should be possible to tell if a drug is effective within just two or three years of trials.
Targeting the V2 receptor is not the only approach being explored. Last year a team led by Ellis Avner of the Rainbow Babies and Children鈥檚 Hospital in Cleveland, Ohio, showed that drugs blocking cell proliferation by targeting the molecular receptor for epidermal growth factor also slow the disease in mice. Avner hopes pilot trials of one of these drugs in people with PKD will begin later this year.