Regrowing livers with gene therapy.
That surprising claim has now led to a provocative new strategy for gene therapy. Investigators led by Markus Grompe of the Oregon Health Sciences University in Portland report that, under the proper conditions, they can exploit the liver's unique regenerative ability-transplanting fewer than 1,000 healthy liver cells completely regenerates the livers of mice suffering from a disease similar to the Norwegian patients' deficiency. The investigators also found that they can cure such mice by adding functioning FAH genes to just a small percentage of their livers' defective cells.
In a commentary accompanying the report of Grompe and his colleagues in the March Nature Genetics, James M. Wilson of the Institute for Human Gene Therapy at the University of Pennsylvania in Philadelphia writes that their work "breathes new life into the prospects of liver-directed gene therapy." "It's a very impressive demonstration that combines basic science and therapy-oriented research," adds gene therapy investigator Gary J. Nabel of the University of Michigan in Ann Arbor.
Gene therapy targeted to the liver has been hampered by delivery problems. Investigators generally use viruses to carry therapeutic genes into cells. Though certain viruses can infect the whole liver, the extra genes they bring in work only for a short time. Other viruses allow long-term operation of therapeutic genes but infect less than 5 percent of a liver-not enough to cure most diseases.
In transplants of liver cells from healthy mice into FAH-deficient rodents, Grompe's group showed that FAH-making liver cells have a natural growth advantage over the defective cells. And since the frequent cell death produced by enzyme deficiency sends the liver into a vigorous regeneration phase, a thousand or so healthy cells can quickly regrow a normal liver. The investigators also injected viruses carrying the FAH gene into diseased livers. Multiple injections, which investigators estimate corrected less than 1 percent of the organ's FAH-defective cells, restored liver function in almost all the mice. "The biology favors the survival of the corrected cells. It's amazing how few cells you have to hit," says Grompe.
Before trying this strategy in humans with FAH-deficiency, Grompe plans to determine if the treated mice develop liver cancer-an eventual result of FAH-deficiency if the enzyme's absence has not already destroyed the liver. This novel gene therapy approach may also be useful for more common genetic diseases of the liver, even ones in which corrected cells do not normally have a growth advantage. Investigators might add to the liver cells a mix of therapeutic genes and genes that confer resistance to a toxic drug. The researchers would then use that drug to damage the liver and let the protected, corrected cells repopulate the organ. "There are all sorts of ways we can envision giving cells a selective advantage," says Grompe.