Liver cirrhosis is reverted by urokinase-type plasminogen activator gene therapy

Liver cirrhosis represents a worldwide health problem and is a major cause of mortality. Cirrhosis is the result of extensive hepatocyte death and fib rosis induced by chronic alcohol abuse and hepatitis B and C viruses. Succe ssful gene therapy approaches to this disease may require both reversal of fibrosis and stimulation of hepatocyte growth. Urokinase-type plasminogen a ctivator (uPA) may serve this function, as it is an initiator of the matrix proteolysis cascade and induces hepatocyte growth factor expression. In a rat cirrhosis model, a single iv administration of a replication-deficient adenoviral vector encoding a nonsecreted form of human uPA resulted in high production of functional uPA protein in the liver. This led to induction o f collagenase expression and reversal of fibrosis with concomitant hepatocy te and improved liver function. Thus, uPA gene therapy may be an effective strategy for treating cirrhosis in humans.