ADA deficiency leads to severe immunodeficiency disease in which T lymphocytes and B lymphocytes do not develop properly. Lack of ADA leads to a 100-fold increase in the cellular concentration of dATP, a strong inhibitor of ribonucleotide reductase.

High levels of dATP produce a general deficiency of other dNTPs in T lymphocytes. The basis for B-lymphocyte toxicity is less clear. Individuals with ADA deficiency lack an effective immune system and do not survive unless treated.

Current therapies include bone marrow transplants from a matched donor to replace the hematopoietic stem cells that mature into B and T lymphocytes. However, transplant recipients often suffer a variety of cognitive and physiological problems. Enzyme replacement therapy, requiring once- or twice-weekly intramuscular injection of active ADA, is effective, but the therapeutic benefit often declines after 8 to 10 years and complications arise, including malignancies.

For many people, a permanent cure requires replacing the defective gene with a functional one in bone marrow cells. ADA deficiency was one of the first targets of human gene therapy trials in 1990 in the US. Mixed results in early trials have given way to significant successes, and gene therapy is rapidly becoming a viable path for long-term restoration of immune function for these patients.