2021
DOI: 10.1016/j.omtm.2021.10.008
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Multiplex CRISPR/Cas9 genome editing in hematopoietic stem cells for fetal hemoglobin reinduction generates chromosomal translocations

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Cited by 30 publications
(27 citation statements)
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“…In recent years, progress on the knowledge of molecular mechanisms involved in Hb switching, the concept of HPHF, combined with epidemiological and clinical observations has provided important evidence on the beneficial role of increasing HbF levels in ameliorating the clinical complications of β-thalassemia and SCD [17]. This can be achieved by either classic drug-modulating approaches or by gene therapy and genome-editing approaches [18][19][20][21][22][23][24]. Although encouraging and promising results have been reported on gene therapy/genome editing and HbF expression, their safety is still to be determined and their expected costs are to be considered as well [25][26][27].…”
Section: Introductionmentioning
confidence: 99%
“…In recent years, progress on the knowledge of molecular mechanisms involved in Hb switching, the concept of HPHF, combined with epidemiological and clinical observations has provided important evidence on the beneficial role of increasing HbF levels in ameliorating the clinical complications of β-thalassemia and SCD [17]. This can be achieved by either classic drug-modulating approaches or by gene therapy and genome-editing approaches [18][19][20][21][22][23][24]. Although encouraging and promising results have been reported on gene therapy/genome editing and HbF expression, their safety is still to be determined and their expected costs are to be considered as well [25][26][27].…”
Section: Introductionmentioning
confidence: 99%
“…Mutations of a single or several nucleotides in human genome are responsible for major hereditary health problems ( Benusiglio et al, 2021 ; Samuelson et al, 2021 ; Xiao et al, 2021 ; Chen et al, 2022 ; Cobo et al, 2022 ). To date, about 7,000 hereditary diseases are estimated to be caused by monogenic mutations ( Claussnitzer et al, 2020 ).…”
Section: Introductionmentioning
confidence: 99%
“…To maximize HbF production, these CRISPR-Cas9-based gene editing approaches can be combined, as recently proposed by Han et al and by Samuelson et al [ 39 , 40 ], who reported on a multiplex gene editing strategy based on the combination of two single gene editing approaches, one aimed at silencing the BCL11A repressor, the other aimed at disrupting the BCL11A binding sites present within the γ-globin gene promoter. Another example of multiplex gene editing approaches is that recently published by Psatha et al [ 41 ], who studied the combination of CRISPR-Cas9-based cis and trans fetal globin reactivation mutations, demonstrating that this strategy leads to a significant increase in HbF production when comparison was performed with the single editing procedures.…”
Section: Introductionmentioning
confidence: 99%
“…The advantage of this strategy is that both protocols use the same target cells (CD34 + erythroid progenitors) and no differences are expected in the clinical steps to be followed for collecting the CD34 + cells to be gene edited and for preparing the patients for the infusion of gene-edited cells (e.g., stem cells collected via mobilization and apheresis, myeloablative conditioning, infusion of corrected stem cells for the engraftment and immune reconstitution) [ 29 ]. On the other hand, a major drawback is expected, i.e., higher off-targeting effects and genotoxicity [ 40 ]. Supporting a caution in using multiplexed CRISPR-Cas9-based approaches, Samuelson et al recently reported that multiplex CRISPR-Cas9 genome editing in hematopoietic stem cells for fetal hemoglobin reinduction generates chromosomal translocations [ 40 ].…”
Section: Introductionmentioning
confidence: 99%
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