Purpose of the Study. To investigate the application of somatic gene therapy for X-linked severe combined immunodeficiency (SCID-X1) in patients without an HLA-matched donor for bone marrow transplant.
Study Population. All 4 children with SCID-X1 resulting from a γ-c chain mutation and without an HLA-identical sibling referred to Great Ormond Street Hospital (London, United Kingdom) between July 2001 and December 2002 were offered and consented to receive gene therapy.
Methods. The complete coding region of human γ-c was cloned into a pMFG gammaretroviral vector and transfected into bone marrow CD34+ stem cells for reinfusion into the patients. T-cell function was assessed by responses to mitogens, Candida antigen, and mixed lymphocyte reactions. T-cell receptor (TCR) repertoires were assessed by direct immunofluorescence with fluorochrome-conjugated antibodies to TCRV-β. Somatic hypermutation was expressed as the fraction of κ light-chain polymerase chain reaction product with mutations preventing cleavage by Fnu4HI.
Results. At reinfusion, 27% to 58% of cells were CD34-positive and γ-c–positive. In all patients, natural killer cells appeared 2 to 4 weeks postinfusion and remained at low-normal levels. Naive CD45RO−, CD27+ T cells appeared at 10 to 30 weeks. Two patients developed normal numbers of CD3, CD4, and CD8 cells, allowing discontinuation of prophylactic medications. One of these patients developed a maculopapular rash on the palms and soles after CD4 T-cell recovery. Another patient had gastrointestinal bleeding resulting from rejection of engrafted maternal cells. The eldest patient, who received gene therapy at 33 months of age, had slower lymphocyte recovery. All patients developed normal T-cell–proliferative responses to mitogens, antigens, and mixed lymphocyte reactions. One year after treatment, all patients showed normal TCRV-β usage and polyclonality within individual V-β families. Two patients maintained normal immunoglobulin levels after discontinuing replacement, and normal serologic responses to vaccines were documented in 1 patient. Somatic mutation demonstrated by mutated V-κ A27 transcripts increased from <2.0% to 5.3% to 23.3% by 1 to 2 years after gene therapy. No pathologic clonal expansions or insertions near the T-cell protooncogene LMO-2 were detected.
Conclusion. After somatic gene therapy, all 4 patients with SCID-X1 had significant improvement in clinical and immunologic function without serious adverse events.
Reviewer Comments. Morbidity and mortality are high in patients with SCID-X1 for whom an HLA-matched family donor is not available. This small study suggests that substantial, prolonged immunologic recovery is possible with somatic gene therapy; however, recovery of thymopoiesis may be compromised in older patients. Previous studies have shown more serious adverse events, including enhancer-mediated activation of the T-cell protooncogene LMO-2. Additional longitudinal studies will help to determine the duration of reconstitution and quantify the risk of adverse events.
- Copyright © 2006 by the American Academy of Pediatrics