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Gene Therapy Combats Hereditary Blood Disease

The treatment suggests that the approach could be used to treat more common disorders.
September 16, 2010

In the most successful demonstration of the potential of gene therapy as a treatment for complex hereditary diseases, the approach has been used to treat a blood disorder called thalassemia that occurs in thousands of people worldwide.

Gene therapy has suffered some well-publicized ups and downs over the past decade, but the past few years have proven it to be a viable–and powerful–option for treating genetic disease. Until recently, however, the most successful attempts have addressed serious disorders that are also relatively rare.

Thalassemia is a genetic disease in which the body doesn’t produce enough hemoglobin, the iron-containing protein in red blood cells responsible for ferrying oxygen throughout the body. In the most serious cases, people require bone marrow transplants (if a match can be found) or frequent blood transfusions just to stay alive. Three years ago, researchers in Paris used gene therapy to treat an 18-year-old patient with a more severe form of the disease. Now, in research published yesterday in the journal Nature, the team reports that this patient has remained relatively healthy and transfusion-free for 21 months.

Gene therapy works on the theory that a genetic disorder can be treated by replacing the gene that causes disease with a “corrected” version. For the current study, scientists removed bone marrow stem cells from a patient with a form of thalassemia called beta-thalassemia, cultured the cells, and used a lentivirus to insert a healthy, working version of the gene. (Lentiviruses, like HIV, are a subtype of retrovirus that work well for gene therapy–they can insert themselves into the genome of both dividing and nondividing cells, correcting as many cultured cells as possible.)

The researchers, led by Philippe Leboulch, a geneticist at Brigham and Women’s Hospital in Boston, then gave the patient a dose of chemotherapy to kill off his original population of bone marrow stem cells and injected the corrected ones back in. The patient’s revised stem cells repopulated his bone marrow, and the revised versions now make up about 10 to 15 percent. Levels of globin (the oxygen-bearing part in hemoglobin) are about two-thirds the normal level–in other words, the patient is mildly anemic–but his condition is not life-threatening.

“We are three years after the treatment, and for 21 months he hasn’t received any transfusions,” Leboulch says.

The concept of gene therapy has excited great expectations over the past few decades, but public enthusiasm has been dampened by a few widely publicized failures. One of the early human trials, in 1999, resulted in a teen’s death and prompted a rapid evaluation of the underlying technology. In another study, four of the 10 children treated with gene therapy for severe combined immunodeficiency disease (SCID, or “bubble boy” syndrome) developed leukemia; as it turned out, the corrected gene was inserted too close to a cancer-causing gene, which it activated.

“The history of gene therapy is a skewed history, and has been shaped partly by the field and a tendency to expect too much too quickly,” says Theodore Friedmann, a professor of pediatrics at the University of California, San Diego, and past president of the American Society of Gene Therapy.

But despite setbacks, and perhaps because of them, researchers have been moving cautiously yet steadily forward and proving gene therapy to be a viable method for treating disease. In addition to other, more successful SCID gene therapy treatments, scientists last year showed that the technique could also be used to treat a rare but fatal brain disease. The new research heralds a movement toward the use of gene therapy for more common genetic diseases. “It’s a very good piece of work, and it’s important because it extends the technology to a more widespread and worldwide disease–I’m very impressed with it,” Friedmann says.

“The results are very encouraging for the field,” says Derek Persons, an experimental hematologist at St. Jude Children’s Research Hospital in Memphis, Tennessee, who is working toward a similar therapy and plans to collaborate with Leboulch on an upcoming study. The results, he says, are the result of nearly three decades of work by multiple labs around the world–but they’re just the start. He points out that Leboulch’s patient had some functional hemoglobin production already. Not enough to survive without transfusions, but enough that the additional activity of the inserted gene brought him up to manageable levels. “If you started from zero,” where the most severe thalassemia patients are, “it would be a lot harder,” he says.

Leboulch and his collaborators will closely watch their first patient to make sure that he remains healthy and stable. They remain cautious, as the vector they used to insert the revised DNA seems to have also caused increased production of a protein associated with benign tumors. They are collaborating with a Cambridge, Massachusetts, company, Bluebird Bio, and if their first patient remains stable, they’ll start a second patient on the therapy early next year, with the goal expanding the trial to 10 patients in 2012. And because sickle-cell disease is so closely related, Leboulch hopes to use the same modified genetic vector in patients with sickle-cell anemia, also starting in 2012.

“This opens avenues to be able to treat genetic diseases in a permanent manner with one shot,” Leboulch says. “And we can also learn from this how to apply similar approaches to noninherited diseases, including cancer. It opens up a lot of possibilities.”

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