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, sbe 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/muL pre-gene therapy versus a mean of 1995/muL 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. Both patients have tolerated the treatments without complication and are able to participate fully in school and social activities. These findings demonstrate that infusions of polyclonal autologous T cells metabolically corrected by ADA gene transfer can be an effective treatment for some children with ADA-severe combined immunodeficiency.