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Targeted deletion of BCL11A gene by CRISPR-Cas9 system for fetal hemoglobin reactivation: A promising approach for gene therapy of beta thalassemia disease.
Journal article

Targeted deletion of BCL11A gene by CRISPR-Cas9 system for fetal hemoglobin reactivation: A promising approach for gene therapy of beta thalassemia disease.

  • Khosravi MA Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. Electronic address: mkhosravi96@gmail.com.
  • Abbasalipour M Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
  • Concordet JP Museum National D'Histoire Naturelle, INSERM U1154, CNRS UMR 7196, Sorbonne Universites, 43 Rue Cuvier, Paris, F-75231, France.
  • Berg JV Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland.
  • Zeinali S Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
  • Arashkia A Department of Virology, Pasteur Institute of Iran, Tehran, Iran.
  • Azadmanesh K Department of Virology, Pasteur Institute of Iran, Tehran, Iran.
  • Buch T Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland. Electronic address: Thorsten.buch@uzh.ch.
  • Karimipoor M Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. Electronic address: mortezakarimi@pasteur.ac.ir.
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  • 2019-05-01
Published in:
  • European journal of pharmacology. - 2019
BCL11A
Beta-thalassemia
CRISPR-Cas9 genome editing tool
Fetal hemoglobin
K562 cell line
γ-globin
Base Sequence
CRISPR-Cas Systems
Carrier Proteins
Fetal Hemoglobin
Gene Deletion
Gene Editing
Genetic Therapy
Humans
K562 Cells
Nuclear Proteins
Repressor Proteins
beta-Thalassemia
gamma-Globins
English Hemoglobinopathies, such as β-thalassemia, and sickle cell disease (SCD) are caused by abnormal structure or reduced production of β-chains and affect millions of people worldwide. Hereditary persistence of fetal hemoglobin (HPFH) is a condition which is naturally occurring and characterized by a considerable elevation of fetal hemoglobin (HbF) in adult red blood cells. Individuals with compound heterozygous β-thalassemia or SCD and HPFH have milder clinical symptoms. So, HbF reactivation has long been sought as an approach to mitigate the clinical symptoms of β-thalassemia and SCD. Using CRISPR-Cas9 genome-editing strategy, we deleted a 200bp genomic region within the human erythroid-specific BCL11A (B-cell lymphoma/leukemia 11A) enhancer in KU-812, KG-1, and K562 cell lines. In our study, deletion of 200bp of BCL11A erythroid enhancer including GATAA motif leads to strong induction of γ-hemoglobin expression in K562 cells, but not in KU-812 and KG-1 cells. Altogether, our findings highlight the therapeutic potential of CRISPR-Cas9 as a precision genome editing tool for treating β-thalassemia. In addition, our data indicate that KU-812 and KG-1 cell lines are not good models for studying HbF reactivation through inactivation of BCL11A silencing pathway.
Language
  • English
Open access status
green
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/260715
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