ADA (Adenosine Deaminase) Deficiency

The treatment of choice for ADA deficiency is bone marrow transplantation from a matched sibling donor. Successful bone marrow transplants can relieve ADA deficiency. Unfortunately, only 20–30% of patients with ADA deficiency have a matched sibling donor. Another treatment involves injecting the patient with PEG-ADA, polyethylene glycol-coated bovine ADA derived from cows. The PEG coating helps keep the ADA from being prematurely degraded. Supplying the missing enzyme in this way helps some patients fight infections, while others are helped very little.

The latest treatment for ADA deficiency is gene therapy. Gene therapy provides victims with their own T cells into which a normal copy of the human ADA gene has been inserted. ADA deficiency is the first disease to be treated with human gene therapy.

The first person to receive gene therapy for ADA deficiency was four-year-old Ashanthi DeSilva. The treatment was developed by three physicians—W. French Anderson, Michael Blaese, and Kenneth Culver. DeSilva received her first treatment, an infusion of her own T cells implanted with normal ADA genes, on September 14, 1990 at the National Institutes of Health in Bethesda, Maryland.

How did DeSilva's T cells acquire the normal ADA genes? A. Dusty Miller of the Fred Hutchinson Research Center in Seattle, Washington, made the vectors for carrying the normal ADA genes into the T cells. These vectors were made from a retrovirus, a type of virus that inserts its genetic material into the cell it infects. By replacing harmful retroviral genes with normal ADA genes, Miller created the retrovirus vectors to deliver the normal ADA genes into DeSilva's T cells. The retrovirus vectors—carrying normal ADA genes—were mixed with T cells that had been extracted from DeSilva's blood and grown in culture dishes. The retrovirus vectors entered the T cells and implanted the normal ADA genes into the T-cell chromosomes. The T cells were then infused back into DeSilva's blood where the normal ADA genes in them produced ADA.

When doctors saw that DeSilva benefited and suffered no harmful effects from gene therapy, they repeated the same treatment on nine-year-old Cynthia Cutshall on January 30, 1991. Both girls developed functioning immune systems. However, since T cells have a limited life span, DeSilva and Cutshall needed to receive periodic infusions of their genetically-corrected T cells, and they both continued with PEG-ADA injections.

Subsequent research is focusing on developing a permanent cure for ADA deficiency using gene therapy. In May and June of 1993, Cutshall and three newborns with ADA deficiency received their own stem cells that had been implanted with normal ADA genes. Unlike T cells which only live for a few months, stem cells live throughout the patient's life, and thus the patient should have a lifetime supply of ADA without requiring further treatment.