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.

I documenti presenti in Iris Unimore sono rilasciati con licenza Creative Commons Attribuzione - Non commerciale - Non opere derivate 3.0 Italia, salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Powered by IRIS-about IRIS-Utilizzo dei cookie

 Copyright © 2021