Gene Therapy May Have Cured 3 Infants
After 10 years of research on more than 4,000 subjects, gene therapy researchers may finally have reached their Holy Grail--curing a patient with a genetic disease.
French researchers have successfully treated three infants with severe combined immunodeficiency disease, a devastating disorder that shuts down children’s immune systems and forces them to live in airtight bubbles to prevent infections.
Dr. Alain Fischer and his colleagues at Hospital Necker-Enfants Malades in Paris removed bone marrow cells from the infants, treated the cells with a virus that carried the gene for a missing protein and returned the cells to the infants’ bodies.
Today, the children all have fully functioning immune systems, and two have lived normal lives for nearly a year, Fischer said at a news conference Thursday in Paris. The research is reported in today’s Science.
“This is the most dramatic improvement in a patient’s condition that has been achieved using gene therapy to date--a real milestone,” said Dr. Jennifer Puck of the National Human Genome Research Institute in Bethesda, Md.
“It’s too early to say if they have been completely cured,” she said, “but for now, they seem to be doing just as well as if they had been cured.”
The achievement was good news for gene therapy researchers, who have been laboring under the shadow of the treatment-related death of 18-year-old Jesse Gelsinger in November at the University of Pennsylvania. That death and subsequent investigations revealed a number of improprieties--albeit relatively minor ones--in the conduct of several gene therapy studies. Some programs were shut down, at least temporarily, while research protocols were revised to better protect participants.
But while those problems have generated headlines, researchers have made several significant improvements in gene therapy efforts. At least two groups of researchers have reported alleviating the symptoms of hemophilia with gene therapy and others have claimed success in growing new blood vessels to bypass blocked arteries in the leg and the heart.
The news from Paris “is coming at a very good time for the field,” said Dr. Katherine High of Children’s Hospital of Philadelphia, who has conducted hemophilia studies. “Most people believe that the underlying principles [of gene therapy] are sound and that it is a question of working out the details. It has proven to be a much more complex undertaking than was initially imagined . . . but Fischer has illustrated that it can be done.”
Dr. W. French Anderson of USC, one of the pioneers in the field, said: “It does look like gene therapy might finally be turning the corner.”
The three male infants treated by Fischer’s group suffer from a rare affliction called severe combined immunodeficiency disease (SCID) X1. It is caused by a defective gene on the X chromosome, one of the chromosomes that determine gender. Because of the faulty gene, the body cannot produce an important protein called the gamma-c cytokine receptor subunit. The lack of that protein, in turn, means that white blood cells cannot be converted into the T, B and natural killer cells necessary for fighting off infections. The infants are left defenseless.
Infants Serve as Their Own Donors
Researchers estimate that the disorder occurs in one of every 50,000 to 100,000 births. The figure could actually be substantially higher, Puck said, because many victims die of infections before the disorder can be diagnosed.
Victims generally live in sterile plastic bubbles for the first year or so of their lives, then receive bone marrow transplants to provide functioning immune cells. If an infant has a closely matched sibling, which happens in about one-fifth of all cases, the transplants are effective about 90% of the time. But if a parent or nonrelative is used as the donor, transplants work only 60% to 70% of the time.
“Gene therapy would allow the infants to serve as their own donor,” leading to a high success rate, said Dr. Donald Kohn of Childrens Hospital Los Angeles.
An even rarer form of the immune disorder is caused by a defect in a different gene, called adenosine deaminase, or ADA. Anderson, Kohn and others have attempted to cure ADA deficiency with gene therapy, but those efforts have been only partially successful and the children have continued to require supplemental drug therapy to replace the missing enzyme. Supplemental therapy is not possible with the form of the disease the French doctors treated.
Fischer’s group initially treated two boys, ages 8 months and 11 months. Doctors removed bone marrow from the boys and isolated stem cells--the primitive cells from which all other blood cells are derived--from each. They grew the cells in a laboratory dish containing fibronectin, a protein thought to make them more receptive to gene therapy.
They then treated the cells with a virus containing the healthy version of the gene that is defective in SCID X1 and infused the cells back into the boys’ bloodstreams. Those cells proliferated in the boys’ bodies, out-reproducing the cells with the defective gene.
Within 15 days, the boys’ bodies began producing T, B and natural killer cells. Diarrhea and skin lesions that had afflicted one of the boys disappeared. Within three months, the babies were able to go home, freed from their bubbles. They have subsequently remained healthy for 11 months and have successfully been vaccinated against tetanus, diphtheria and polio--vaccinations that would not have worked before their treatment.
A third boy was subsequently treated and has now been healthy for four months.
“The clinical benefits we observe have never been achieved before,” Fischer said at the news conference.
Kohn said: “This is a real home run for gene therapy.”
Puck cautioned that the long-term success of the therapy will not be known for at least a couple more years. A child’s immune system does not normally become fully developed until somewhere between the ages of 3 and 5, so Fischer’s success cannot be fully evaluated until the children are at least that old, she said.
“This is a major step toward being able to do the same thing for kids with sickle cell disease, thalassemia and other problems,” Kohn said. “SCID is the easiest to treat, because a few cells can grow out to produce a whole immune system,” but this shows that the concept will work, he said.
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Gene Therapy Milestone
French researchers have used gene therapy to apparently cure three infants with severe combined immunodeficiency, which leaves the children defenseless against infections.
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Source: Science
