Gene therapy rebuilds immunity and its image

LONDON — There is something about gene therapy that captures the media's and the public imagination, and this week's announcement by Great Ormond Street Children's Hospital in London, that two babies had been treated successfully — not necessarily cured — for a severe, life threatening disease of the immune system was no exception. Except for similar work undertaken by French researchers in 2000, the public perception of gene therapy has been that the reality did not match the hype and aspiration. In particular, public confidence was shaken in September 1999 when a young man, Jesse Gelsinger, died during a US clinical trial of gene therapy for a liver disease. Though the nature of this trial, being in vivo, was very different from the ex vivo work of the French group and now Great Ormond Street, gene therapy in lay eyes lost some of its shine.Now, though, the field is once again seen as promising. Encouraging results continue to emerge from basic research, as well as from this newest clinical work at Great Ormond Street. Led by clinical immunologist Adrian Thrasher, the group at Great Ormond Street focused on a type of immune disease known as severe combined immuno deficiency-X1 (SCID)-X1 caused by a defect in the gamma c gene on the long arm of the X chromosome. (This is exactly the same disease as that targeted by the French group). The gene defect, which affects about 1 in 100 000 live births, is more common in boys because they have only one X chromosome.As a result of the defect, T cells and natural killer (NK) cells essential for fighting off infection do not differentiate from earlier progenitor cells. The problem arises because the gamma c gene encodes a polypeptide subunit common to the interleukin 2,4,7,9 and 15 receptors, and these receptors are part of the cell signaling mechanism that leads to the growth, survival and differentiation of the early progenitor cells into the fully differentiated T and NK cells. Infants diagnosed with SCID-X1 must be isolated from all possible causes of disease. "We have known what the problem is since the early 1990s," says Christine Kinnon, a molecular immunologist, Thrasher's colleague and chair of the Institute of Child Health at Great Ormond Street. But knowing the problem and solving it turned out to be two very different things. Prior to the French work (led by Marina Cavazzana-Calvo and Alain Fischer at INSERM in Paris) and Thrasher's, the only cure was to replace the defective bone marrow with that of a healthy donor. But suitable donors are hard to find. Spurred by this fact, researchers have sought to develop a way to replace the faulty gamma c gene. The approach taken by Great Ormond Street — and other researchers interested in ex vivo gene therapy — was to extract a sample of bone marrow from the patient, then to cultivate the sample with a retrovirus carrying a normal copy of the defective gene. The hope is that the retrovirus will insert itself into the DNA of the patient's pluripotent stem cells (transduce the cells). These cells have the potential to differentiate into all the cell types of the immune system, and the idea is that once incorporated into the stem cell's DNA, the normal gene could do its task of producing the polypeptide needed to ensure the chemicals for cell signaling can complete their task of orchestrating differentiation of the progenitor cells and subsequent growth of the T and NK cells.Although the theory sounds straightforward, the procedure is difficult in practice for a number of reasons connected with basic stem cell biology. For example, for the retrovirus to transduce a host cell, the cell must be dividing. Therefore the trick is to stimulate stem cell division but prevent differentiation into progenitor cells. The gene could transduce the progenitor cells also, but these might not be as long lived as the stem cells, and they would not give rise to all types of immune system cell.Trial and error in the laboratory has established seemingly effective methods to overcome this obstacle, said Kinnon, but no-one really knows just how many stem cells are transduced and thus for how long the new immune system will be produced. Nevertheless, because the treatment can be repeated if necessary, it is very promising. Equally encouraging are results from Cavazzana-Calvo and Fischer, says Kinnon. Their patients were treated using a similar approach (with a slightly different retrovirus package) three years ago and they still have functioning immune systems.Now Great Ormond Street plans to apply its technique to other forms of SCID. The next clinical trials will be on X-linked chronic granulomatous disorder (CGD). This disease is caused by the lack of a single gene, gp91phox, which means that a type of white blood cell, known as a neutrophil, cannot do its job of protecting against bacterial and fungal infections. Antibiotics can prolong life for CGD patients but only a bone marrow transfusion supplies a cure.The clinical trial for CGD will be riskier than for SCID-X1 because the five children who will participate will have to undergo chemotherapy to prevent production of the neutrophils that do not work. In SCID-X1, where no T and NK cells are produced, such a draconian procedure was not needed.Further down the road, the team hopes to tackle yet another form of SCID, known as SCID-ADA. This is the disease that was the first to be treated using gene therapy by the pioneer, French Anderson, in 1990. The girl treated is still alive and carries a corrective gene, but she is also taking a conventional therapy and it is unclear which keeps her healthy. Trials by Great Ormond Street and others should give some answers.

Gene therapy rebuilds immunity and its image

Researchers at Great Ormond Street Children's Hospital strengthen the case for gene therapy as a treatment for immunodeficiencies.

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