Gene therapy takes aim at liver, lungs.

Gene therapy takes aim at liver, lungs

Two studies released last week describe progress in an experimental technique that may someday replace organ or tissue transplants as a means of correcting certain metabolic disorders. In both cases, researchers are using recombinant DNA technology to correct for a class of diseases in which one or more defective genes result in an inability to produce particular proteins in the body.

Savio L. C. Woo of the Baylor College of Medicine in Houston reports that he and his colleagues successfully infected liver cells with recombinant retroviruses, and that these viruses directed the liver cells to produce a new protein. The research points to the possibility of stimulating genetically defective liver cells to produce normal proteins by using custom-crafted viruses as genetic delivery vehicles --a process known as somatic gene therapy.

"The liver may be the preferred target for somatic gene therapy of many inborn errors of metabolism that are currently indications for liver transplant,' the researchers write in the August PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (Vol. 84, No. 15).

The research, however, confirms the importance of incorporating the proper genetic "switch,' or promoter, into a genetically engineered carrier virus in order to get expression of an inserted gene. Working with liver cells cultured from mice, the researchers experimented with three different viral promoters. They found that only one of them--the herpes TK promoter--was capable of being "turned on' in liver cells. "That's in contrast to skin cells,' says one of the researchers, Fred D. Ledley, "where all three promoters work just fine.'

The research is aimed at developing a treatment for one of the most common inborn errors of metabolism--phenylketonuria, or PKU (SN: 2/8/86, p.84), in which liver cells fail to produce the protein phenylalanine hydroxylase. Each year in the United States about 1 in 12,000 infants is born with the deficiency, which carries potential for toxicity and mental retardation.

"These kids can be kept on a [phenylalanine-free] diet, but that's palliation, not a cure,' Ledley told SCIENCE NEWS. In addition, he says, "There are really dozens of liver disorders--many of which are lethal--that we just can't treat.' Although liver transplants are becoming increasingly successful, Ledley notes that "the key advantage of gene therapy over organ transplants is that you don't need to find a donor.'

In related research, scientists at the National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, Md., transplanted gene-altered cells into mice, then tracked the long-term production of a human protein by those cells. The cells had been induced via retroviral gene transfer to produce alpha

1-antitrypsin, a protein that protects lung tissue from naturally occurring but potentially damaging enzymes. Inherited deficiencies of alpha 1-antitrypsin today account for 20,000 to 40,000 cases of emphysema in the United States.

Robert I. Garver Jr. and his colleagues report in the Aug. 14 SCIENCE that alpha 1-antitrypsin diffused into the blood and lung tissue of mice for four weeks after genetically engineered alpha 1-antitrypsin-producing cells were injected into the rodents' abdominal cavities. The research suggests that physicians may someday treat genetic deficiencies of certain circulating proteins by implanting "colonies' of specially engineered protein-secreting cells.

These findings differ from those of Woo and others at Baylor, who found that the addition of PKU-correcting protein to the general circulation was insufficient to correct that genetic deficiency. The difference, according to Ronald G. Crystal of the NHLBI team, may be that phenylalanine hydroxylase--the PKU protein --needs to interact with cofactors inside liver cells, while alpha 1-antitrypsin works in the extracellular space. "I think the approach we're using can be useful for conditions in which the deficient protein is an extracellular protein, such as alpha 1-antitrypsin, growth hormone, or complement [an immune system protein].'

In addition, Crystal says, his team's technique may prove more useful than the current practice--also still experimental --of using bone marrow cells to manufacture missing proteins. Instead of using marrow cells, which are genetically variable and can respond to gene transfers in unpredictable ways, the team uses monoclonal fibroblast cells that are genetically uniform and that express inserted genes more efficiently.