For the first time, doctors have used gene therapy to stave off a fatal degenerative brain disease, an achievement that some experts had thought impossible.
The key to making the therapy work? One of the medicine’s greatest villains: HIV.
The patients were children who had inherited a mutated gene causing a rare disorder, adrenoleukodystrophy, or ALD. Nerve cells in the brain die, and in a few short years, children lose the ability to walk or talk.
They become unable to eat without a feeding tube, to see, hear or think. They usually die within five years of diagnosis.
The disease strikes about one in 20,000 boys; symptoms first occur at an average age of 7. The only treatment is a bone-marrow transplant — if a compatible donor can be found — or a transplant with cord blood, if it was saved at birth.
But such transplants are an onerous and dangerous therapy, with a mortality rate as high as 20 percent. Some who survive are left with lifelong disabilities.
Now a new study, published online in the New England Journal of Medicine, indicates that gene therapy can hold off ALD without side effects, but only if it is begun when the only signs of deterioration are changes in brain scans.
The study involved 17 boys (the disease strikes males almost exclusively), ages 4 to 13. All got gene therapy. Two years later, 15 were functioning normally without obvious symptoms.
“To me, it seems to be working,” said Dr. Jim Wilson, director of the gene therapy program at the University of Pennsylvania’s Perelman School of Medicine, who was not involved in the new study.
One of the remaining two boys died; his disease progressed so rapidly that gene therapy could not stop it. The other withdrew from the study in order to have a bone-marrow transplant. He died of complications from the procedure.
The study opens new avenues for using gene therapy to treat brain diseases, said Dr. Theodore Friedmann, a gene therapy pioneer at the University of California San Diego School of Medicine.
“Many think the central nervous system is intractable and unapproachable,” he said. This study proves them wrong.
The research began with a determined mother, Amber Salzman, who was an executive with a Ph.D. in mathematics at GlaxoSmithKline. In 2000, her nephew was diagnosed with ALD, a disease she had heard of only in the movie, “Lorenzo’s Oil.”
He was “this wonderful sweet brilliant kid,” Dr. Salzman said. “All of a sudden he loses his abilities. He crumbles in front of your eyes.”
She had her one-year-old son tested and found that he had the mutated gene, as did another nephew. She looked into Lorenzo’s oil, a difficult dietary regimen featuring a specially designed oil.
Statisticians at her company told her studies of it did not show any effect.
Dr. Salzman met with Dr. Tachi Yamada, who was head of research and development at Glaxo. “I said, ‘It will be a few years before the bomb goes off in my son and other nephew. What do we do?’”
Dr. Yamada told her that her best bet was gene therapy, but it had never been tried against a disease like ALD.
Indeed, gene therapy had recently fallen out of favor after 18-year-old Jesse Gelsinger died during an experimental treatment. Then, in 2003, four of nine children who got gene therapy for an immunodeficiency disease developed leukemia.
Dr. Salzman, with assistance from her sister, Rachel, and from other scientists, was undeterred. She corralled researchers worldwide, asking why a different sort of virus couldn’t be used to slip a good ALD gene into the boys’ cells.
The best choice, it turned out, was a disabled form of HIV, which can insert genes into human cells more safely than other viral carriers.
Scientists were understandably wary. Disabled AIDS viruses had not been used in human gene therapy. But “I don’t take no for an answer,” Dr. Salzman said. “I probably come just shy of stalking people.”
The result of her lobbying was a tiny study in France in which researchers used a disabled form of HIV to deliver a normal form of the ALD gene. The investigators reported that the treatment seemed to stop brain degeneration in two boys.
Yet the idea behind the treatment seems almost preposterous: Take bone marrow stem cells from a boy with the ALD gene mutation. Insert a good gene into those cells and then infuse them back into the bone marrow.
Wait about a year while stem cells with the good genes multiply in the bone marrow. Eventually, they drift up into the brain, where they slowly turn into glial cells — support cells that surround neurons and help insulate them.
The proper gene in the glial cells takes over, stopping the brain deterioration that would otherwise occur.
That unlikely process also explains why bone marrow transplants work, said David A. Williams, chief scientific officer at Boston Children’s Hospital and a principal investigator for the study. New bone marrow cells, from a healthy donor, supply good ALD genes to cells in the recipient that eventually become glial cells.
Either therapy must be administered early, before symptoms are apparent. In the year it takes for the treatment to become effective, the brains of children who are already showing symptoms can deteriorate to the point of no return.
The success of the small pilot study was enough to inspire the founding of a company, Bluebird Bio, which sponsored the bigger study in hopes of marketing gene therapy for ALD.
The company has now expanded that study to include an additional eight boys, and in separate research is following boys who had bone marrow transplants to compare outcomes.
For Paul Rojas of Dover Plains, N.Y., whose son was in the study, gene therapy has been a lifesaver. He never heard of the disease until his son Brandon, who was 7, started drooling, losing his ability to concentrate and listing to one side when he walked.
The diagnosis was a shock. And since Brandon was showing symptoms, it was too late for a bone-marrow transplant.
Brandon’s doctors, Mr. Rojas said, sat across from him and his wife, Liliana, in a small conference room and gave them the bad news: “This is a disease that has no cure.”
He had his 4-year-old, Brian, tested. He had the mutated gene, too.
The Rojases could not find a compatible donor for a bone-marrow transplant. But then they learned about the gene therapy trial and got Brian enrolled. He is now 7, with no sign of the disease.
But his older brother Brandon, now 10, no longer speaks, walks or eats. He has a feeding tube.
“Brian misses playing with his brother,” Mr. Rojas said. “Brandon was his idol.”
For Dr. Salzman, the results of the new gene therapy study have come too late. She had to get treatment for her son before he developed symptoms.
He had a cord blood transplant, which was successful. Her nephew also had one, but suffered complications and must use a wheelchair.
The results of the new study also give rise to a concern that is becoming a regular feature of gene therapy work and other new biotech therapies: How much will this treatment cost?
Bluebird Bio is not saying – companies generally do not announce prices until their drugs are approved.
Dr. David A. Williams, chief scientific officer at Boston Children’s Hospital and a principal investigator of the new study, expects the price to be similar to the hundreds of thousands of dollars it costs for a bone-marrow transplant.
But the new treatment “is a curative therapy,” he said.
Dr. Friedmann is not assuaged by such arguments. The research enabling these products to come to market often begins with studies already paid for by grants from the federal government or from private foundations.
The expected prices, he said, are “absolutely crazy.”