A previously published clinical trial demonstrated the benefit of autologous CD34+ cells transduced with a selfinactivating
lentiviral vector (HPV569) containing an engineered β-globin gene (βA-T87Q-globin) in a subject with β
thalassemia major. This vector has been modified to increase transduction efficacy without compromising safety. In vitro
analyses indicated that the changes resulted in both increased vector titers (3 to 4 fold) and increased transduction efficacy
(2 to 3 fold). An in vivo study in which 58 β-thalassemic mice were transplanted with vector- or mock-transduced syngenic
bone marrow cells indicated sustained therapeutic efficacy. Secondary transplantations involving 108 recipients
were performed to evaluate long-term safety. The six month study showed no hematological or biochemical toxicity. Integration
site (IS) profile revealed an oligo/polyclonal hematopoietic reconstitution in the primary transplants and reduced
clonality in secondary transplants. Tumor cells were detected in the secondary transplant mice in all treatment groups (including
the control group), without statistical differences in the tumor incidence. Immunohistochemistry and quantitative
PCR demonstrated that tumor cells were not derived from transduced donor cells. This comprehensive efficacy and safety
data provided the basis for initiating two clinical trials with this second generation vector (BB305) in Europe and in the
USA in patients with β-thalassemia major and sickle cell disease.
Keywords: β-hemoglobinopathy, β-thalassemia, gene therapy, lentiviral vector, mouse model.
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