Aiuti A, Slavin S, Aker M, et al. Science. 2002;296:2410–2413
Purpose of the Study.
To use improved gene therapy techniques to correct adenoside deaminase (ADA)-deficient severe combined immunodeficiency (SCID).
Two patients (7 months old and 2.5 years) with ADA-SCID who lacked an HLA-identical sibling donor and for whom polyethylene glycol conjugated (PEG)-ADA was unavailable.
Patients underwent collection of autologous CD34+ cells (stem cells) from bone marrow that were corrected for ADA by transduction using a retroviral vector and infused 4 days later. Patients received nonmyeloablative treatment with busulfan.
Both patients experienced immune reconstitution (although the infant showed a swifter and more complete response). Genetically corrected granulocytes, monocytes, megakaryocytes, and erythroid cells were detected, T cell responses normalized, antibody production was corrected, and specific responses to vaccination were documented. Infections also abated. Red blood cell toxic metabolites declined and liver enzyme abnormalities resolved. The less complete response of the older patient was attributed to a lower dose of transfected cells, less myeloablation, and possibly an effect of his older age.
A combined approach of using autologous genetically corrected stem cells and nonmyeloablative conditioning allowed more complete restoration of immune and metabolic functioning in ADA-SCID patients than has been previously achieved.
ADA leads to the accumulation of toxic metabolites that cause immune cell death and results in SCID. Previous studies of therapy using genetically corrected peripheral blood lymphocytes (PBLs) and exogenous ADA in the form of PEG-ADA to support immune function lead to poor engraftment of the corrected cells possibly because there was not a sufficient survival advantage for these cells in the presence of exogenous ADA. When PEG-ADA was not given, full correction was still not achieved, indicating that such correction may require a more global therapy, not just infusion of genetically corrected PBLs. This study shows that rather amazing immune reconstitution was possible with the successful engraftment of multipotent, genetically corrected stem cells, and provides hope for more definitive therapy for this and other disorders.