Study Shows Hope for Gene Therapy

Study Shows Hope for Gene Therapy

Researchers have launched a new gene-therapy trial for children with a rare disease known as “bubble boy syndrome,” reflecting fresh hopes that the strategy of delivering working genes can be used to treat many intractable ailments.

In the new study, sponsored in the U.S. by investigators at Children’s Hospital Boston and expected to open at five sites around the world, scientists plan to enroll 20 boys with SCID-X1, which stands for severe combined immunodeficiency, X-linked—a genetic condition that affects boys and leaves them unable to fight germs. Without treatment, which is currently possible only by bone-marrow transplantation, most children die before age one.

The study comes seven years after two similar trials in Europe—one in Paris and one in London, involving a total of 20 children—were temporarily halted when two participants were diagnosed with leukemia. Three others eventually developed the blood cancer, and one died. Those who survived were cured of SCID-X1, but the episode prompted the U.S. Food and Drug Administration to put a hold on certain gene-therapy studies.

While gene-therapy studies in other diseases have gone forward, the new trial is the first involving SCID-X1 to take place in the U.S. since the hold. Researchers believe they have stripped out the feature of the treatment that caused leukemia.

“If the trial is successful, we think what we are doing can apply to other rare diseases as well,” said David Williams, chief of hematology/oncology at Children’s Hospital Boston and lead investigator for the U.S. sites.

In gene therapy, scientists try to correct a problem caused by a defective or non-functioning gene. A normal gene is delivered via what scientists call a vector, typically a virus genetically altered to contain human DNA. The idea is that this normal gene will begin producing a protein that has been missing or not working and cure the disease.

The earlier SCID-X1 trials, along with the death in 1999 of 18-year-old Jesse Gelsinger four days after starting gene therapy at the University of Pennsylvania for a different genetic condition, intensified regulatory scrutiny and dampened enthusiasm for the new technology. Some scientists began to wonder whether gene therapy was too risky and too complex to become a safe and effective treatment.

But recent findings from several studies are rekindling excitement for the approach. Last fall, a team led by researchers at Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine reported they had successfully injected a gene via a genetically engineered vector into the retinas of 12 patients suffering from a blindness-causing genetic disease called Leber’s congenital amaurosis. All patients had some improvement in eyesight.

In another report last year, European researchers said they successfully delivered a gene into the blood cells of two patients with a rare, fatal brain disease called X-linked adrenoleukodystrophy (ALD). Patrick Aubourg, professor of pediatrics at University Paris Descartes, said the treatment halted progression of the disease. Three years later, the patients remain stable and can attend school.

The preliminary findings helped Genetix Pharmaceuticals Inc., of Cambridge, Mass., raise $35 million in venture capital to finance additional research, said Nick Leschly, the company’s interim president.

The data in these and other reports involve small numbers of patients, but “we’re seeing the first evidence of real therapeutic efficacy,” said Susan Robinson, chief executive officer of Seattle-based Targeted Genetics Corp., which is involved in an ongoing gene-therapy trial in Britain for Leber’s congenital amaurosis.

In the new SCID-X1 trial—which is open in London and Boston and undergoing regulatory review in Los Angeles, Cincinnati and Paris—researchers will take stem cells from a patient’s own bone marrow, deliver a functioning gene into those cells in the lab and then infuse them back into the patient. If all goes well, the cells will start producing a protein that will multiply and provide a functioning immune system.

Currently, SCID-X1 is treatable only by bone-marrow transplantation, preferably from a sibling who is an exact bone-marrow match. When successful, that halts progression of the disease. But patients who must resort to marrow from unmatched donors require chemotherapy and face other serious complications.

So gene therapy, if successful, could not only avoid the need for chemotherapy but correct the genetic defect in one treatment. “The possibility of curing a disease possibly forever after only one treatment is really amazing,” says Dr. Williams of Children’s Hospital Boston.

Dr. Williams wasn’t involved in the original trial, but helped found the Transatlantic Gene Therapy Consortium seven years ago to set a new course for SCID-X1 trials following the leukemia problems. The group—including researchers from the UCL Institute of Child Health in London, Necker Hospital in Paris and Hannover Medical School in Germany—has vetted data, devised new laboratory experiments and redesigned the vehicle delivering the normal gene.

As part of the redesign, the parts of the vector thought to have activated leukemia-causing genes have been taken out. The researchers successfully tested the new vector in animals and in lab studies and believe the problem has been eliminated, says Luigi Notarangelo, the site investigator for the trial at Children’s Hospital Boston. Study participants will be monitored for 15 years to rule out any cancer risk.

The disease is very rare—fewer than one in 200,000 babies are born with the X-linked version of SCID each year—so the consortium adopted a common protocol to try to enroll patients more quickly.

Meantime, St. Jude Children’s Research Hospital, Memphis, Tenn., is planning a separate gene-therapy trial for infants with SCID-X1. The St. Jude’s researchers developed their own viral vector they say will lower the risk of leukemia. The investigators are hoping to begin enrollment in late 2010 or early 2011, a spokeswoman said.

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