After setbacks, small successes for gene therapy


POSTED: Friday, November 06, 2009

Not long ago, gene therapy seemed troubled by insurmountable difficulties. After decades of hype and dashed hopes, many who once embraced the idea of correcting genetic disorders by giving people new genes all but gave up the idea.

But scientists say gene therapy may be on the edge of a resurgence. There were three recent, though small, successes—one involving children with a fatal brain disease, one with an eye disease that causes blindness and one with children who have a disease that destroys the immune system.

“;We are ready to move,”; said Dr. Luigi Naldini of the Institute for Gene Therapy at Vita-Salute San Raffaele in Milan.

Dr. Kenneth Cornetta, a gene therapy researcher at Indiana University and president of the American Society of Gene and Cell Therapy, added: “;It's exciting. The science gets better every year.”;

But given the history of gene therapy, some, like Dr. Mark Kay, a gene therapy researcher at Stanford, were careful to avoid promising too much.

The field was dealt a blow when the first gene therapy success, reported six years ago, turned out to have a problem. Eighteen of 20 children with a rare genetic disease were cured, but then three of the children developed leukemia and one died of it. Researchers and gene therapy companies became skittish.

“;I like to be really cautious,”; Kay said. But now, he added, “;there is a lot of reasonably cautious optimism.”;

The latest encouraging news arises from a paper published Friday in the journal Science. An international team of researchers is reporting the successful treatment of two children with adrenoleukodystrophy, or ALD, in which the fatty insulation of nerve cells degenerates. A result is progressive brain damage and death two to five years after diagnosis. The disease was the focus of the movie “;Lorenzo's Oil.”;

Scientists say they believe they avoided the cancer problem by using a different method to get genes into the children's DNA. Two years have gone by, and the children are doing well.

The children were not cured, but their disease was arrested. And gene therapy was as good as the standard treatment, a bone marrow transplant. In this case, the children could not have a transplant because they did not have marrow donors who were genetic matches.

In addition, a paper last month in the journal Lancet reported that a different method of gene therapy, which did not involve inserting a new gene into DNA, partly restored the sight of five children and seven adults with a rare congenital eye disease, Leber's congenital amaurosis. People with the disease have a mutated gene that prevents them from making a retina protein.

While not in the DNA, the added gene remains in the body of the cells, directing the production of the missing protein and helping correct the disorder. The patients had no standard treatment, and gene therapy offered them a chance to see again, although their sight was far from perfect. But the gene is not copied when cells divide, as it would be if it were part of the cells' DNA, so the method applies only to cells, like those of the retina, that divide rarely.

And a paper in The New England Journal of Medicine a year ago reported that 8 out of 10 patients with a rare immunological disorder were cured with gene therapy. The method was the same as the one that led to leukemia, and Cornetta said scientists were still studying why it did not cause cancer in those children.

The paper in Science was accompanied by an editorial by Naldini titled, “;A Comeback for Gene Therapy.”; In a telephone interview, he added that the result was “;pushing a lot of people to move forward,”; including him.

The story of gene therapy for ALD began when Amber Salzman of Merion Station, Pa., learned that her nephew had the disease. Since it is a genetic disorder, the entire family was tested. A second nephew had the gene, and, Salzman learned, so did her 1-year-old son.

The disorder progresses slowly and relentlessly. “;I knew we had four, maybe five, years to come up with a treatment,”; she said.

Salzman and her sisters got to work, forming the Stop ALD Foundation and pushing scientists and doctors to meet and plan a study of gene therapy.

It turned out that several groups of researchers had been developing a new way to get genes into a cell's DNA. The original method used a modified mouse leukemia virus to insert genes. That method was used in the study in France that led to leukemia in some children.

And the virus was unsuitable anyway for most diseases because it corrected gene defects in only 0.1 percent of cells. That, many said, was a worse problem than the leukemia.

Researchers were stymied, said the lead investigator of the ALD study, Dr. Patrick Aubourg of Inserm, an institute for health and medical research in France.

The new approach involved using HIV, the virus that causes AIDS, to insert genes, modifying the virus first so it could not cause disease.

“;We were scared, of course,”; said Naldini, who was working on the virus in the laboratory of Dr. Inder Verma at the Salk Institute. But he reasoned that if he could remove enough HIV genes to make it safe, the modified virus could work.

It solved the efficiency problem—the modified AIDS virus added genes to 15 percent of cells. And researchers believe it solved the cancer problem. The modified AIDS virus had much less chance of turning on genes that could lead to cancer.

Salzman and Lapin found out about the work and contacted Verma.

“;These sisters were so driven,”; Verma said. “;They were passionate about it. They certainly got me there.”;

In the end, the company Cell Genesys made the virus, and Aubourg treated two boys from Spain.

Salzman's son had a bone marrow transplant. Her sister's older boy died of ALD, and her younger son underwent a bone marrow transplant but had complications from the procedure and now, successfully treated for ALD, is in a wheelchair from side effects of the transplant.

Aubourg has already treated a third boy with ALD. The child is doing well, but it is too soon to know if his disease has been arrested.

“;We have to be cautious—very, very cautious,”; Aubourg said. “;But this is the first time that a very serious disease of the brain, a lethal disease of the brain, has been treated with success by gene therapy.”;