Gene Therapy Hope in Liver Disease

A group of researchers in San Diego has successfully transplanted foreign genes into liver cells, raising the possibility of eventually treating hemophilia and other genetic disorders of the liver through the emerging techniques of gene therapy.

Their report of the work, to be published later this month in the Proceedings of the National Academy of Sciences, is the first published instance of successful introduction and expression of foreign genes in liver cells.

Scientists had succeeded previously in inserting genes into bone marrow cells. But the new technique may open the door to treating genetic disorders that affect the liver, including phenylketonuria (PKU) and diseases of fat and cholesterol metabolism.

“What it suggests is that the liver is an organ that might be susceptible to deliberate genetic change to correct a genetic defect,” said Dr. Theodore Friedmann, a professor of pediatrics at UC San Diego and a co-author of the forthcoming paper.

The idea of gene therapy--transferring normal genes into patients suffering from genetic disorders--has emerged over the last decade as scientists have developed techniques of isolating and manipulating genes and inserting them into cells.

Insertion is done with the help of specially engineered tumor viruses, called retroviruses, that can infect normal cells and splice foreign genes into those cells. The infected cells thus incorporate--and, in theory, express--the new gene.

Researchers hope that eventually the techniques of gene therapy may offer cures for at least a few of the more than 3,000 known genetic diseases. Among those cited as potential candidates for therapy have been hemophilia, cystic fibrosis and sickle-cell anemia.

Over the last 18 months, Friedmann and others working at UCSD developed a technique for inserting and expressing several foreign genes in rat liver cells in culture. As in past research, they used specially tailored retroviruses to deliver the genes to the cells.

“It was a chancy experiment, in a way,” Friedmann said. He said past research in young mice had indicated that liver cells were not susceptible to infection by these retroviruses.

But Dr. Jon Wolff and other co-authors of the paper discovered a brief time period during which cultured liver cells become susceptible to infection. Exploiting that brief window during the cells’ development, they managed to infect them with the retrovirus.

“The common consensus was that you couldn’t do it,” said Wolff, an assistant professor of pediatrics and principal author on the paper. “ . . . We show that you can put genes into normal liver cells, efficiently and stably.”

That makes “thinkable” the idea of gene therapy through the liver, Wolff said.

One disease that might be susceptible to treatment is hemophilia, in which patients’ blood fails to clot and abnormal bleeding occurs. Others include hypercholesterolemia, which causes excessive cholesterol in the blood.

However, gene therapy in humans is years away, the researchers said. Before they can try the technique on humans, they must move from cell cultures to animal studies and prove that the foreign genes can be transferred and expressed in animals.

Bone Marrrow Diseases

Eventually, Wolff said, researchers hope to be able to take a patient with a certain genetic disease, remove some of his or her liver cells, grow them in culture, insert the normal gene through the retrovirus technique, and inject the improved cells back into the patient.

Much of the past work toward gene therapy has centered on diseases of the bone marrow, because bone marrow is easily accessible and is the seat of many important diseases such as leukemia and sickle-cell anemia.

While it has proven feasible to put foreign genes in bone marrow cells, Friedmann said it turns out to be difficult and inefficient. Gene expression has proven to be relatively weak in experimental animals and appears to decline over time, he said.

Friedmann said Tuesday that it remains to be seen whether gene expression in the case of liver cells will prove more efficient.