Development of gene therapy for immunodeficiency: adenosine deaminase deficiency.
Deficiency of adenosine deaminase (ADA) results in severe combined immunodeficiency. Clinical cure has been observed in several ADA-severe combined immunodeficiency patients after bone marrow transplantation in which only donor T cells were engrafted, suggesting that T-cell correction alone is sufficient for full immune reconstitution. Children without an HLA-matched donor have been treated with polyethylene glycol-ADA as enzyme replacement therapy, resulting in varying degrees of immunologic and clinical improvement. In September 1990, we began treating a 4-y-old girl with periodic infusions of autologous culture-expanded T cells genetically corrected by insertion of a normal ADA gene using retroviral-mediated gene transfer with the LASN vector. After 2 y of polyethylene glycol-ADA treatment and before gene therapy, she continued to experience recurrent infections, was anergic and lymphopenic, and was deficient in isohemagglutinins. After seven infusions totaling 7 x 10(10) T cells, she has demonstrated a substantial increase in the number of circulating T cells (571/microL pre-gene therapy versus a mean of 1995/microL with gene therapy infusions every 6-8 wk) and the ADA activity in her peripheral blood T cells has increased > 10-fold. The increase in T-cell numbers and ADA activity has been associated with the development of positive delayed-type hypersensitivity skin tests, a significant increase in the level of isohemagglutinins, the regrowth of tonsils, and a decreased number of infectious illnesses. This improvement has persisted during suspension of treatment for more than 6 mo. A second patient treated since February 1991 has shown similar improvement in immune status.(ABSTRACT TRUNCATED AT 250 WORDS)
Blaese
R M
RM
Cellular Immunology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics / Q000627:therapeutic use; D000818:Animals; D016026:Bone Marrow Transplantation; D002648:Child; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000201:enzymology; D014161:Transduction, Genetic
D000243:Adenosine Deaminase; C051409:pegademase bovine