Starting in 2006, French researchers performed ex vivo lentiviral gene therapy on two boys with X-linked adrenoleukodystrophy, a fatal brain disease caused by loss of the ABCD1 gene. This gene plays an important role making myelin, the fatty sheath that insulates neurons. Without ABCD1, the brain can’t send electrical messages properly.

The boys received a transfusion of their own modified blood stem cells. Two years after the therapy, about 15 percent of their blood stem cells carried the fixed version of ABCD1. Their brain cells had started making insulated neurons and the damage ceased. Although the boys still have some cognitive difficulties, the therapy saved their lives.

In 2007, some of the same researchers used the approach on an 18-year-old man with ß-thalassemia, a genetic disease that prevented him from making healthy red blood cells, which carry oxygen throughout the body. The man had received a blood transfusion every month since he was 3 years old.

After receiving the gene therapy, he started making his own healthy blood. “He has not received one drop of blood for three years,” says Philippe Leboulch, professor of medicine and cell biology at the University of Paris and visiting professor at Harvard Medical School, an investigator in both studies. “He has a full-time job as a cook in a Paris restaurant, he has a girlfriend, he feels good.” Leboulch plans to transplant a second ß-thalassemia patient this fall.

The right vector for the job

Every gene therapy strategy has pros and cons. So far, ex vivo approaches haven’t run into a major immune response. But because their vectors are permanently inserted in the host’s genome, they could inadvertently turn on cancer genes.

In the ß-thalassemia trial, for example, the lentivirus turned on expression of a protein called HMGA2, which has been linked to benign and malignant cancers. “It’s something that the field is well aware of and that we need to improve upon,” Leboulch says.

He knew the surgery was the right decision four days after Corey left the hospital, when the family took a trip to the zoo and Corey said that the sun was hurting his eyes. “That had never happened before. It was a pretty big deal.”

Ethan Haas

Cancer is less of a concern with the AAV vector used in the eye trials because most of it stays outside the genome. Because it doesn’t integrate into the DNA, however, it’s not useful in cells that constantly divide, such as those in the blood, skin, and intestine. And, of course, AAV’s capsid envelope brings about that unwanted immune reaction.

Several groups are at work fine-tuning the AAV vector so that it’s more efficient, delivering more of the target gene with less exposure to the viral capsids. High’s group, for example, is collaborating with researchers from St. Jude Children’s Research Hospital, Stanford University, and University College London to test a modified AAV vector that may reduce the immune response in people with hemophilia.

She’s also working on a different approach in which, rather than adding a healthy gene, a molecular knife—called a zinc finger nuclease—corrects the broken gene. These fingers have received much attention in the past couple of years, since High’s colleagues at Penn began using them to alter an immune system gene ex vivo in blood cells of patients with HIV. In a study of mice with hemophilia, published June 26, 2011, in Nature, High’s group reported the first demonstration that zinc fingers can also work their magic inside a living animal.

“Zinc fingers have several advantages over AAVs,” High says. Perhaps most notably, they correct genes inside the stretch of the genome where they belong, meaning that normal cellular cues will be able to turn them on and off when necessary.

Still, High says that in the short term, hemophilia patients are more likely to benefit from AAV approaches. “I know how long it is from a mouse study to a clinical trial that works,” she says.

Down the line, it’s likely that the field will be choosing from a range of vectors and using both in vivo and ex vivo approaches, depending on the disease, according to Kay. “There’s not going to be one vector that’s going to be perfect for all applications. They all have their niche.” (See sidebar, “Taking Down Bad Genes.”)

The AAV procedure, for example, transformed Corey’s life. His father, Ethan Haas, knew the surgery was the right decision four days after Corey left the hospital, when the family took a trip to the zoo and Corey said that the sun was hurting his eyes. “That had never happened before. It was a pretty big deal,” Ethan recalls. But best of all, he says, was the day Corey tried out the maze. “To see him navigating this obstacle course without difficulty—it was the most dramatic thing.”

In the two years since, Haas says he’s been pressing the researchers to repeat the procedure in Corey’s other eye. He’s slated for surgery this fall.

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