ADA (Adenosine Deaminase) Deficiency
Treatments for ADA deficiency
ADA deficiency is an inherited condition that occurs in fewer than one in 100,000 live births worldwide. Individuals with ADA deficiency inherit defective ADA genes and are unable to produce the enzyme adenosine deaminase in their cells. The ADA gene consists of a single 32 kb locus containing 12 exons and is located on the long arm of chromosome 20. The enzyme adenosine deaminase is needed to break down metabolic byproducts that become toxic to T-cell lymphocytes, and is essential to the proper functioning of the immune system. Most of the body's cells have other means of removing the metabolic byproducts that ADA helps break down and remain unaffected by ADA deficiency. However, T-cell lymphocytes, white blood cells that help fight infection, are not able to remove the byproducts in the absence of ADA.
Without ADA, the toxins derived from the metabolic byproducts kill the T cells shortly after they are produced in the bone marrow. Instead of having a normal life span of a few months, T cells of individuals with ADA deficiency live only a few days. Consequently, their numbers are greatly reduced, and the body's entire immune system is weakened. ADA deficiency is the first known cause of a condition known as severe combined immunodeficiency (SCID).
The body's immune system includes T-cell lymphocytes and B-cell lymphocytes; these lymphocytes play different roles in fighting infections. B cells produce antibodies that lock on to disease-causing viruses and bacteria, thereby marking the pathogens for destruction. Unlike B cells, T cells cannot produce antibodies, but they do control B cell activity. T-cell helpers enable antibody production, whereas T-cell suppressors turn off antibody production. Another T-cell subtype kills cancer cells and virus-infected cells.
Because T cells control B cell activity, the reduction of T cells results in an absence of both T cell and B cell function called severe combined immunodeficiency (SCID). Individuals with SCID are unable to mount an effective immune response to any infection. Therefore, exposures to organisms that normal, healthy individuals easily overcome become deadly infections in SCID patients. Prior to present-day treatments, most ADA-deficient SCID victims died from infections before reaching the age of two. Although SCID is usually diagnosed in the first year of life, approximately one-fifth of ADA deficient patients have delayed onset SCID, which is only diagnosed later in childhood. There are also a few cases of ADA deficiency diagnosed in adulthood.
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.
Lemoine, Nicholas R., and Richard G. Vile. Understanding Gene Therapy New York: Springer-Verlag, 2000.
Hershfield, M.S., Mitchell, B.S. "Immunodeficiency Diseases Caused by Adenosine Deaminase Deficiency and Purine Nucleoside Phosphorylase Deficiency." In: Scriver, C.R.; Beaudet, A.L.; Sly, W.S.; Valle, D., eds) The Metabolic and Molecular Bases of Inherited Disease, 7th ed. Vol. 2. New York: McGraw-Hill 1995.
Blaese, Michael R. "Development of Gene Therapy for Immunodeficiency: Adenosine Deaminase Deficiency." Pediatric Research 33 (1993): S49–S55.
Thompson, Larry. "The First Kids With New Genes." Time (7 June 1993): 50–51.