gene therapy

Gene therapy: Treating the bubble babies

21/11/02. By the Public Health Genetics Unit

Children with severe combined immunodeficiency have been treated using gene therapy.

The first ever gene therapy trials were initiated in 1990 by Dr William French Anderson. The patient was a four-year-old girl called Ashanthi who was suffering from a very rare disease known as severe combined immunodeficiency (SCID). In Ashanthi's case, the disease was caused by the absence of the enzyme adenosine deaminase (ADA). This deficiency prevented her body from producing the lymphocytes (B-cells and T-cells) that are required to fight off infections.

Before the advent of gene therapy, there were two ways to treat ADA-SCID. The first was regular injections with the ADA enzyme, administered as a mixture with polyethylene glycol (PEG) to increase its stability. The second was a bone marrow transplant from a compatible donor. If neither of these treatments was possible, the only way affected children could survive was by total isolation in an artificial, germ-free environment. For this reason, children suffering from SCID are often known as 'bubble babies'.

ADA deficiency was an ideal target for the first gene therapy trials for a number of reasons:

  • the pathological effects of the disease are reversible
  • the disease results from the loss of function of a single gene
  • ADA levels vary widely in the normal population so tight control of the introduced gene is not important
  • the ADA gene is very small and easy to manipulate in the laboratory
  • the target cells for the therapy are lymphocytes, which are accessible, easy to culture and easy to put back into the body of the patient
  • the alternative treatments are expensive and/or hazardous.

Unfortunately, the effects of Ashanthi's gene therapy were short lived. For ethical reasons ADA-PEG enzyme therapy was continued during the trial, but once this treatment was withdrawn, the symptoms of the disease returned. She still requires the enzyme today.

Further trials were initiated in which bone marrow cells or umbilical cord blood cells were used as targets. These contain the stem cells that produce lymphocytes throughout our lives. The modification of these stem cells did result in the long-term production of a small number of ADA-positive lymphocytes. However, the levels of ADA produced by the cells were low and it is not clear whether the patients would survive without concurrent ADA-PEG treatment.

In 2002 there was a major breakthrough in ADA gene therapy. This resulted from the use of a technique called non-myeloblative conditioning, in which bone marrow in the SCID patient is partially killed in order to give the modified stem cells the chance to proliferate. Another important factor was that none of the children in this trial had been treated with ADA-PEG. It appears that enzyme treatment may have contributed to the lack of success in previous gene therapy trials.

The first patient was a two-year-old Palestinian child called Salsabil who had never received ADA-PEG therapy. The new treatment seems to have cured her condition and Salsabil is now living at home with her parents and enjoying a normal life. Her body is producing antibodies and she has even managed to fight off chicken pox, which would almost certainly have killed her only months earlier.

Article courtesy of the Public Health Genetics Unit .

Image credit: University of Edinburgh

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