Naturally occurring, large deletions in the b-globin locus result in hereditary persistence of fetal hemoglobin, a condition that mitigates the clinical severity of sickle cell disease (SCD) and b-thalassemia. We designed a clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) strategy to disrupt a 13.6-kb genomic region encompassing the d- and b-globin genes and a putative g-d intergenic fetal hemoglobin (HbF) silencer. Disruption of just the putative HbF silencer results in a mild increase in g-globin expression, whereas deletion or inversion of a 13.6-kb region causes a robust reactivation of HbF synthesis in adult erythroblasts that is associated with epigenetic modifications and changes in chromatin contacts within the b-globin locus. In primary SCD patient-derived hematopoietic stem/progenitor cells, targeting the 13.6-kb region results in a high proportion of g-globin expression in erythroblasts, increased HbF synthesis, and amelioration of the sickling cell phenotype. Overall, this study provides clues for a potential CRISPR/Cas9 genome editing approach to the therapy of b-hemoglobinopathies.

Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human b-globin locus / Antoniani, C.; Meneghini, V.; Lattanzi, A.; Felix, T.; Romano, O.; Magrin, E.; Weber, L.; Pavani, G.; Hoss, S. E.; Kurita, R.; Nakamura, Y.; Cradick, T. J.; Lundberg, A. S.; Porteus, M.; Amendola, M.; Nemer, W. E.; Cavazzana, M.; Mavilio, F.; Miccio, A.. - In: BLOOD. - ISSN 0006-4971. - 131:17(2018), pp. 1960-1973. [10.1182/blood-2017-10-811505]

Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human b-globin locus

Romano O.;Mavilio F.;Miccio A.
2018

Abstract

Naturally occurring, large deletions in the b-globin locus result in hereditary persistence of fetal hemoglobin, a condition that mitigates the clinical severity of sickle cell disease (SCD) and b-thalassemia. We designed a clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) strategy to disrupt a 13.6-kb genomic region encompassing the d- and b-globin genes and a putative g-d intergenic fetal hemoglobin (HbF) silencer. Disruption of just the putative HbF silencer results in a mild increase in g-globin expression, whereas deletion or inversion of a 13.6-kb region causes a robust reactivation of HbF synthesis in adult erythroblasts that is associated with epigenetic modifications and changes in chromatin contacts within the b-globin locus. In primary SCD patient-derived hematopoietic stem/progenitor cells, targeting the 13.6-kb region results in a high proportion of g-globin expression in erythroblasts, increased HbF synthesis, and amelioration of the sickling cell phenotype. Overall, this study provides clues for a potential CRISPR/Cas9 genome editing approach to the therapy of b-hemoglobinopathies.
131
17
1960
1973
Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human b-globin locus / Antoniani, C.; Meneghini, V.; Lattanzi, A.; Felix, T.; Romano, O.; Magrin, E.; Weber, L.; Pavani, G.; Hoss, S. E.; Kurita, R.; Nakamura, Y.; Cradick, T. J.; Lundberg, A. S.; Porteus, M.; Amendola, M.; Nemer, W. E.; Cavazzana, M.; Mavilio, F.; Miccio, A.. - In: BLOOD. - ISSN 0006-4971. - 131:17(2018), pp. 1960-1973. [10.1182/blood-2017-10-811505]
Antoniani, C.; Meneghini, V.; Lattanzi, A.; Felix, T.; Romano, O.; Magrin, E.; Weber, L.; Pavani, G.; Hoss, S. E.; Kurita, R.; Nakamura, Y.; Cradick, T. J.; Lundberg, A. S.; Porteus, M.; Amendola, M.; Nemer, W. E.; Cavazzana, M.; Mavilio, F.; Miccio, A.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1223163
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