Partial correction of murine β-thalassemia with a gammaretrovirus vector for human γ-globin

Abstract Several studies have demonstrated that recombinant lentivirus vectors containing extended globin gene expression cassettes and regulatory elements can ameliorate the pathogenic sequela in murine models of β-thalassemia and sickle cell disease. Similarly promising results have not yet been obtained with recombinant gammaretrovirus vectors. Of these two vector classes, only gammaretroviruses have been tested extensively in clinical trials, with a proven ability to transduce long-term reconstituting hematopoietic stem cells with an exceedingly low incidence of serious side effects. Toward the continuing goal of developing retrovirus vectors for the treatment of the β-chain hemoglobinopathies, we report here the assessment of a recombinant gammaretrovirus vector for human γ-globin in murine models of β-thalassemia. In the β-thalassemia intermedia Hbb th-3 /+ model, we observed a dose-dependent but transient increase in total hemoglobin and red blood cells, with a 2.5 ± 0.2 g/dL increase in hemoglobin for transduction rates ≥ 33%. In the severe β-thalassemia major Hbb th-3 /Hbb th-3 model, we observed a modest but statistically significant increase in survival, from a median of 15 days to 30 days ( P = 0.001). These studies provide the first evidence that globin gene transfer vectors based on recombinant gammaretroviruses may provide a viable option for the treatment of the β-chain hemoglobinopathies.