BioWorld International Correspondent
LONDON - Gene therapy for an inherited form of immunodeficiency is capable of restoring immune function to almost-normal levels, UK researchers reported, raising hope that it might one day be possible to use gene therapy to treat other inherited disorders of the blood, such as sickle cell anemia and thalassemia.
The inherited immunodeficiency usually is fatal in the first year of life, but four children who underwent the gene-therapy procedure now are living a normal life at home and attending school.
The therapy corrected the condition known as X-linked severe combined immunodeficiency (SCID-1X). Boys who inherit the disorder have a defect in the gene encoding the gamma chain protein, which plays a role in detecting triggers that allow the development of certain cells of the immune system. As a result, those children fail to develop T cells and natural killer cells, which are crucial to an effective immune response.
SCID-1X affects between one in 50,000 to one in 100,000 births. Those with the condition succumb to opportunistic infections and viral illnesses that normal people can fight off. Some children have survived much longer - notably the patient David Vetter, who lived in a "bubble" for 12 years to avoid catching infections from the environment.
Bobby Gaspar, senior lecturer and consultant in pediatric immunology at the Institute of Child Health in London, told BioWorld International: "As this study shows, we have had initial success with this type of inherited immune deficiency, as have a group working in France. But we hope this will also pave the way for using gene therapy for other inherited disorders of the hematopoietic system, including conditions that are much more common, like sickle cell anemia."
Gaspar and his colleagues, together with UK and international collaborators, reported the study in the Dec. 18, 2004, issue of The Lancet in a paper titled "Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector."
In an accompanying comment on the paper, titled "Efficacy of gene therapy for SCID is being confirmed," Marina Cavazzana-Calvo and Alain Fischer of the H pital Necker-Enfants Malades in Paris, wrote that the four cases described bring to 18 the total number of SCID patients treated by that type of gene therapy. They add: "Remarkably, 17 of these 18 patients had their immunodeficiencies corrected with clear and sustained clinical benefits. The data show that the results of this gene-therapy strategy are reproducible."
Until now, the only treatment for SCID-1X has been bone marrow transplantation. That works well if the child has a donor who is a good match, but both the transplant itself and the preparation can have side effects and complications.
Gaspar and his team have investigated gene therapy as an alternative for those children who do not have a well-matched donor. They took a healthy copy of the gene that is defective in SCID-1X and inserted it into a disabled murine retrovirus.
Next, they took bone marrow cells from each patient and isolated hematopoietic stem cells. The stem cells were then cultured in the presence of the genetically manipulated retrovirus, which inserted the healthy copy of the desired gene into the DNA of the cells.
Each patient then had his own bone marrow stem cells re-infused into his bloodstream. Gaspar said: "Over time, because these bone marrow cells now have a working copy of the required gene, they start to develop into the missing T cells and natural killer cells, and they start to confer immunity and protection against infection."
The treatment avoids the side effects that are associated with a bone marrow transplant, Gaspar added. The team hopes that, by inserting the gene into very early stem cells that have the capacity to self-renew, manufacture of the desired protein will continue for the patients' lifetime - but they will be able to confirm that only by long follow-up.
However, two out of 10 patients treated in Paris developed leukemia. Gaspar said studies had shown that occurred because the virus had inserted its DNA either close to or in an oncogene, so triggering it to manufacture its protein. "We have to balance the benefits of this treatment with the risk," Gaspar concluded. "We are now working on ways of targeting the virus into safe' areas of the chromosome, or changing its structure so that it does not turn on oncogenes."