Publication Date:
2004-11-16
Description:
X-linked severe combined immunodeficiency (XSCID) results from mutations in IL2RG, which encodes the common gamma chain (γc) shared by receptors for IL-2, 4, 7, 9, 15 and 21. XSCID is best treated with bone marrow transplantation (BMT) from an HLA-matched sibling. Patients lacking a matched sibling can benefit from a T-cell depleted haploidentical BMT, but some do not achieve adequate immune reconstitution. Ex vivo autologous hematopoietic stem cell (HSC) gene therapy may be an alternative to haploidentical BMT. In a French trial, 9 of 10 XSCID infants had immune reconstitution following ex vivo transduction of autologous HSC with a retroviral vector encoding γc. Selective development and expansion of T, NK and B cells from progenitors expressing γc was important to the success of this therapy. However, the 2 youngest patients, treated at 1 and 3 months of age, later developed T cell leukemias associated with retrovirus insertions that activated the LMO2 transcription factor. Young age at treatment might have had a role in the development of these adverse events. We have developed an XSCID gene transfer protocol as salvage treatment for older patients who have failed haploidentical BMT. An 11 year-old XSCID patient with no detectable engraftment from prior haploidentical BMTs had lymphocytopenia, growth failure, infections, chronic diarrhea and skin rashes. After G-CSF mobilization and harvest by apheresis, his purified autologous peripheral blood CD34+ cells were transduced daily for 4 days with GALV-MFGS-γc retrovirus in the presence of growth factors and Retronectin®. Eighty million cells/kg (80% CD34+; 40% γc transgene positive) were reinfused. At 1, 2 and 3 months after treatment, provirus marking by PCR of unseparated blood leukocytes was 1.4%, 2.3% and
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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