Washington D.C.- French researchers have developed a method of gene therapy to treat human severe combined immunodeficiency (SCID) X1, a life-threatening disease inherited on the X chromosome. Usually, patients with SCID are forced to live within tightly controlled and sterile "bubbles" to avoid any threats to their nonexistent immune systems until a bone marrow transplant is attempted. The new therapy is described in the 28 April issue of Science.
Two infants, aged 8 and 11 months, were the beneficiaries of this treatment, which provides a normal copy of the defective gene that causes SCID X1 that quickly proliferates within the patient's body. The new gene "unblocks" the development of other immune cells, restoring the immune system to normal functioning. The infants' return to a normal immune system has lasted over eleven months without side effects, says study co-author Alain Fischer of the Hospital Necker in Paris. The Science report notes that a third patient is experiencing similar progress four months after the gene transfer.
The defective gene encodes part of a cell receptor that sends out signals to the parents of T and NK cells, crucial components of the immune system that destroy invaders and rally other immune defenses. Without this gene's direction, these cells do not develop, grow, or spread, and SCID X1 patients are left fatally vulnerable to even slight infectious insults to the body such as a cold sore or common childhood diseases like chicken pox.
The researchers began the therapy by harvesting bone marrow from the patients and sorting out a set of blood stem cells from the marrow. After bathing in a growth factor in containers coated with a fibronectin fragment, a threadlike protein that encourages efficient gene transfer, the cells were infected with a retrovirus carrying the replacement gene. After three days of repeated infection, the scientists transplanted the cells back into the patients without any prior drug treatment. "It was important to show success in the absence of any chemotherapy," explains Fischer.
As early as 15 days later, he and his colleagues detected new cells bearing the correct version of the gene, along with rising numbers of fully functional and diverse immune cells. Currently, the two patients have T, B, and NK cell counts comparable to normal children of their age. The scientists also tested the patients' rebounding immune systems with tetanus, diphtheria, and polio vaccinations, and found that the infants produced the correct antibodies for each.
Fischer believes that the key to the therapy's success lies "not in the technique, but in the disease itself." In the SCID X1 cases, cells with the normal gene seem to enjoy a significant selective advantage, multiplying rapidly until their numbers overwhelm their mutated cousins. Researchers had an inkling of this advantage when one faulty version of the gene spontaneously reversed itself in a previous SCID X1 patient, leading to a lasting rally of the patient's immune system. "This means that even a poorly efficient gene therapy technique--one that only introduces a few cells with the right gene--may work as a treatment," says Fischer, who notes that this might bode well for the success of this therapy for other genetically similar immune diseases.
According to the study, the two young SCID X1 patients have experienced "striking" clinical improvements. No longer in protective isolation, they both live at home without any treatment, enjoying normal growth and development for their ages. Ideally, Fischer says, the children will be monitored for the rest of their lives, both to ensure their continued health and to monitor the long-term success of the therapy.