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EnglishSickle cell disease (SCD) is caused by a mutation in the β-globin gene leading to polymerization of the sickle hemoglobin (HbS) and deformation of red blood cells. Autologous transplantation of hematopoietic stem/progenitor cells (HSPCs) genetically modified using lentiviral vectors (LVs) to express an anti-sickling β-globin leads to some clinical benefit in SCD patients, but it requires high-level transgene expression (i.e., high vector copy number [VCN]) to counteract HbS polymerization. Here, we developed therapeutic approaches combining LV-based gene addition and CRISPR-Cas9 strategies aimed to either knock down the sickle β-globin and increase the incorporation of an anti-sickling globin (AS3) in hemoglobin tetramers, or to induce the expression of anti-sickling fetal γ-globins. HSPCs from SCD patients were transduced with LVs expressing AS3 and a guide RNA either targeting the endogenous β-globin gene or regions involved in fetal hemoglobin silencing. Transfection of transduced cells with Cas9 protein resulted in high editing efficiency, elevated levels of anti-sickling hemoglobins, and rescue of the SCD phenotype at a significantly lower VCN compared to the conventional LV-based approach. This versatile platform can improve the efficacy of current gene addition approaches by combining different therapeutic strategies, thus reducing the vector amount required to achieve a therapeutic VCN and the associated genotoxicity risk.
Combination of lentiviral and genome editing technologies for the treatment of sickle cell disease / Ramadier, S.; Chalumeau, A.; Felix, T.; Othman, N.; Aknoun, S.; Casini, A.; Maule, G.; Masson, C.; De Cian, A.; Frati, G.; Brusson, M.; Concordet, J. -P.; Cavazzana, M.; Cereseto, A.; El Nemer, W.; Amendola, M.; Wattellier, B.; Meneghini, V.; Miccio, A.. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - 30:1(2022), pp. 145-163. [10.1016/j.ymthe.2021.08.019]
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| Titolo: | Combination of lentiviral and genome editing technologies for the treatment of sickle cell disease | |
| Autori: | Ramadier, S.; Chalumeau, A.; Felix, T.; Othman, N.; Aknoun, S.; Casini, A.; Maule, G.; Masson, C.; De Cian, A.; Frati, G.; Brusson, M.; Concordet, J. -P.; Cavazzana, M.; Cereseto, A.; El Nemer, W.; Amendola, M.; Wattellier, B.; Meneghini, V.; Miccio, A. | |
| Autori Unitn: | ||
| Titolo del periodico: | MOLECULAR THERAPY | |
| Anno di pubblicazione: | 2022 | |
| Numero e parte del fascicolo: | 1 | |
| Codice identificativo Scopus: | 2-s2.0-85114361181 | |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1016/j.ymthe.2021.08.019 | |
| Handle: | http://hdl.handle.net/11572/327038 | |
| Citazione: | Combination of lentiviral and genome editing technologies for the treatment of sickle cell disease / Ramadier, S.; Chalumeau, A.; Felix, T.; Othman, N.; Aknoun, S.; Casini, A.; Maule, G.; Masson, C.; De Cian, A.; Frati, G.; Brusson, M.; Concordet, J. -P.; Cavazzana, M.; Cereseto, A.; El Nemer, W.; Amendola, M.; Wattellier, B.; Meneghini, V.; Miccio, A.. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - 30:1(2022), pp. 145-163. [10.1016/j.ymthe.2021.08.019] | |
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