Gene therapy meets liver transplants.

Gene Therapy Meets Liver Transplants

A ground-breaking proposal to seed the failing livers of desperately ill children with healthy, genetically marked liver cells cleared its biggest hurdle last week, receiving provisional approval from a key advisory subcommittee of the National Institutes of Health (NIH).

The experiment would assess the effectiveness of a new cell-transplant technique that could obviate the need for whole liver transplants in some patients. It could also be the first attempt to transplant patients with genetically altered cells that may persist in the body for life. Previous human gene therapy and marker gene experiments (SN: 12/22&29/90, p.388) have involved circulating blood cells, which die off after a few months.

The NIH's Human Gene Therapy Subcommittee conditionally approved the proposal -- submitted by researchers at the Baylor College of Medicine and Texas Children's Hospital in Houston -- to inject up to six patients with liver cells grown in the laboratory and marked with a gene for antibiotic resistance. The gene will allow the researchers to detect the transplanted cells. The researchers expect most of the patients to be children, because few child-sized donor livers are available for transplant.

"We really hope we can get some children through their liver failure and determine if the [cell] transplants work," says Fred D. Ledley, leader of the Houston team. The researchers have tested the cell transplant technique in animals, but the proposed trial will mark the first use of laboratory-cultured liver cells in humans.

Transplanting liver cells, or hepatocytes, could serve as an alternative someday to whole liver transplants in children too small to get livers from larger donors, Ledley says. It could also offer hope to the hundreds of U.S. children and adults each year who die of liver failure before a donor organ can be found.

The researchers plan to inject billions of the altered cells into the primary vein carrying blood to the liver. The marker gene will allow them to determine whether the hepatocytes take up residence in the liver and how long they last. The marker will not have a direct therapeutic effect, although it could help the researchers gauge how long to keep the patients on immune-suppressing drugs.

Eventually, Ledley hopes to adapt the treatment for children with liver-associated metabolic diseases by genetically altering hepatocytes to produce the protein their defective cells cannot.

Two of the nine NIH panel members voted against the Houston team's proposal, saying it had not proved to them the necessity of administering altered genes in order to determine whether the transplant method works. Panelist R. Scott McIvor, a geneticist from the University of Minnesota in Minneapolis, suggested that the researchers instead try to monitor the transplanted cells by looking for distinctive proteins on their surfaces. He also contended that the subcommittee needs more data demonstrating the team's ability to genetically tag human hepatocytes. In the end, the rest of the panel agreed to approve the proposal on the condition that the investigators provide the extra data before starting the experiment.

The Houston team must also win approval from the NIH's Recombinant DNA Advisory Committee, which meets May 31, and from the Food and Drug Administration. In addition, the researchers need the signed approval of the NIH director. "We think we'll be approved to start treating patients by the fall," Ledley says.

Three other gene-marker experiments won provisional approval at last week's subcommittee meeting. These include proposals by two separate teams -- one at the St. Jude Children's Research Hospital in Memphis, Tenn., the other at Houston's M.D. Anderson Cancer Center -- to use genetically tagged bone marrow cells to determine why some marrow transplants fail. The subcommittee also approved a proposal by researchers at the University of Pittsburgh School of Medicine to track tagged cancer-fighting cells infused into the bloodstream.