Reversing polycystic kidney disease in mice

Using mouse models, researchers showed that, in early stages of polycystic kidney disease (PKD), kidney damage can be reversed by reactivating an inactive gene—findings that raise the possibility of using gene therapy to treat people with PKD. PKD is a genetic disorder that causes numerous fluid-filled cysts to grow in the kidneys. Over time, growth of these cysts results in enlarged kidneys in which normal tissue is displaced and kidney function is impaired, sometimes quite severely. The most common form of PKD is autosomal dominant polycystic kidney disease (ADPKD), which results from mutations in either the PKD1 or PKD2 genes. Previous research has shown that therapies targeting molecular pathways affected by disruption of the PKD1 or PKD2 genes can slow progression of the disease, but not reverse the kidney damage.

In a new study, scientists used complex genetic strategies to first inactivate either of the corresponding genes in mice—Pkd1 or Pkd2—specifically in the kidney, which led to enlarged kidneys, characteristic cyst formation, and other forms of damage. They later reactivated the genes relatively early in the course of the disease, which led to a dramatic reduction in kidney size in the mice. Further analyses showed that the gene reactivations reversed many hallmarks of PKD: the cysts resolved, cell and tissue structures returned to normal, and many signs of kidney damage (e.g., inflammation, tissue scarring) dramatically improved. When the scientists waited to reactivate the genes until the mice had reached an advance stage of PKD, they observed partial, but not complete, reversal of disease characteristics, suggesting that eventually some damage from the disease can become permanent. Although kidney damage was once considered almost invariably permanent, this study demonstrates that, in some cases, reversal may be possible, at least in mice. If these findings hold true in humans, gene therapy approaches may one day be able not just to slow disease progression in people with ADKPD, but potentially to reverse it.