Journal
VIRUSES-BASEL
Volume 14, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/v14122716
Keywords
sickle cell disease; thalassemia; globin gene therapy; gamma-globin lentiviral vector; HbF; HPFH enhancers; -117 HPFH type; CD34(+) hematopoietic stem cells
Categories
Funding
- European Commission
- [11?-RARE-09-155]
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This study demonstrates the efficacy of the optimized gamma-globin lentiviral vector in improving the phenotype of sickle cell disease in vitro, highlighting its potential for future clinical trials.
We have previously demonstrated that both the original gamma-globin lentiviral vector (LV) GGHI and the optimized GGHI-mB-3D LV, carrying the novel regulatory elements of the 3D HPFH-1 enhancer and the 3' beta-globin UTR, can significantly increase HbF production in thalassemic CD34(+) cells and ameliorate the disease phenotype in vitro. In the present study, we investigated whether the GGHI-mB-3D vector can also exhibit an equally therapeutic effect, following the transduction of sickle cell disease (SCD) CD34(+) cells at MOI 100, leading to HbF increase coupled with HbS decrease, and thus, to phenotype improvement in vitro. We show that GGHI-mB-3D LV can lead to high and potentially therapeutic HbF levels, reaching a mean 2-fold increase to a mean value of VCN/cell of 1.0 and a mean transduction efficiency of 55%. Furthermore, this increase was accompanied by a significant 1.6-fold HbS decrease, a beneficial therapeutic feature for SCD. In summary, our data demonstrate the efficacy of the optimized gamma-globin lentiviral vector to improve the SCD phenotype in vitro, and highlights its potential use in future clinical SCD trials.
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