Gene Therapy success

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.

blindness“We are ready to move,” said Dr. Luigi Naldini of the Institute for Gene Therapy at Vita-Salute San Raffaele University 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,” Dr. 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 cancerThe 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 Dr. 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 Dr. 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, Ms. Salzman learned, so did her 1-year-old son.

Ms. Salzman and her sisters got to work, forming the Stop ALD FoundationIt 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 H.I.V.“We were scared, of course,” said Dr. Naldini, who was working on the virus in the laboratory of Dr. Inder M. Verma at the Salk Institute. But he reasoned that if he could remove enough H.I.V. 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 virus had less chance of turning on genes that could lead to cancer.

Ms. Salzman and Ms. Lapin found out about the work and contacted Dr. Verma. In the end, the company Cell Genesys made the virus, and Dr. Aubourg treated two boys from Spain.

Ms. 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.

Dr. Aubourg has also treated a third boy with ALD, and he is doing well, but it is too soon to know if his disease has been arrested.

“We have to be cautious — very, very cautious,” Dr. 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.”


By Gina Kolata
Published New York Times, November 5, 2009 A version of this article appeared in print on November 6, 2009, on page A19 of the New York edition.