CRISPR/Cas9 system: A promising technology for the treatment of inherited and neoplastic hematological diseases

Antony, Justin S.; Haque, Aminul; Lamsfus‐Calle, Andrés; Daniel‐Moreno, Alberto; Mezger, Markus; Kormann, Michael

doi:10.1002/acg2.10

Cited by 14 publications

(9 citation statements)

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“…The gamma chain of HbF is encoded by the HBG1/2 genes and transcriptionally controlled by several elements in the β-globin gene cluster. Interestingly, the elevation of HbF by natural-occurring deletions in the β-globin cluster, varying from 13 bp, 7.2 kb (Corfu), 12.9 kb (Sicilian) and 13.6 kb, have been identified in HPFH individuals 7,14,[26][27][28] . Furthermore, previous studies using ChIP-seq and CUT&RUN analyses elucidated the consensus binding site of BCL11A (TGACCA) repressor, situated upstream of the transcription start site of the γ-globin gene (−115 bp) 28,44 .…”

Section: Discussionmentioning

confidence: 99%

“…Though lentiviral gene transfer of β-globin exhibited positive effects in treated β-thalassemia patients 20 , the high volume of semi-random integration sites by lentivirus and the transactivation of the proto-oncogene HMGA2 raised major safety concerns for this approach 21,22 . Due to the afore-mentioned reasons, CRISPR/ Cas9-mediated gene disruption of specific regulators to re-express HbF is a promising alternative 7 . Thus, several studies have targeted various genetic regulators by CRISPR/Cas9 to reactivate HbF expression, resulting in a profound effect after genetic interference of BCL11A, KLF1, and HBG1/2 promoters 14,17,23 .…”

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confidence: 99%

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Comparative targeting analysis of KLF1, BCL11A, and HBG1/2 in CD34+ HSPCs by CRISPR/Cas9 for the induction of fetal hemoglobin

Lamsfus‐Calle

Daniel‐Moreno

Antony

et al. 2020

Sci Rep

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β-hemoglobinopathies are caused by abnormal or absent production of hemoglobin in the blood due to mutations in the β-globin gene (HBB). Imbalanced expression of adult hemoglobin (HbA) induces strong anemia in patients suffering from the disease. However, individuals with natural-occurring mutations in the HBB cluster or related genes, compensate this disparity through γ-globin expression and subsequent fetal hemoglobin (HbF) production. Several preclinical and clinical studies have been performed in order to induce HbF by knocking-down genes involved in HbF repression (KLF1 and BCL11A) or disrupting the binding sites of several transcription factors in the γ-globin gene (HBG1/2). In this study, we thoroughly compared the different CRISPR/Cas9 gene-disruption strategies by gene editing analysis and assessed their safety profile by RNA-seq and GUIDE-seq. All approaches reached therapeutic levels of HbF after gene editing and showed similar gene expression to the control sample, while no significant off-targets were detected by GUIDE-seq. Likewise, all three gene editing platforms were established in the GMP-grade CliniMACS Prodigy, achieving similar outcome to preclinical devices. Based on this gene editing comparative analysis, we concluded that BCL11A is the most clinically relevant approach while HBG1/2 could represent a promising alternative for the treatment of β-hemoglobinopathies. Sickle cell disease (SCD) and β-thalassemia, commonly known as β-hemoglobinopathies, are inherited blood disorders caused by mutations in the human β-globin gene (HBB) 1-4. In healthy condition, adult human hemoglobin (HbA) consists of 2 α and 2 β chains, whereas fetal hemoglobin (HbF) expressed in early gestation comprises 2 α chains and 2 γ chains. Notably, HbF was observed to bind oxygen with greater affinity than HbA, being functional when reactivated in adults 3,5,6. Recent studies have generated substantial experimental evidence that HbF reactivation by gene disruption of specific transcription factors and regulators could provide a therapeutic benefit for β-hemoglobinopathies 7. It has long been appreciated that KLF1 and BCL11A are key regulators involved in the process of γto β-globin switching and the repression of these genes leads to HbF resurgence 6-11. Interestingly, healthy individuals with a benign genetic condition namely hereditary persistence of fetal hemoglobin (HPFH) were observed to exhibit persistent production of functional HbF 4,10,12,13. HPFH is caused by large deletions in the δand β-globin genes, or point mutations in the γ-globin promoter and γ-globin repressors, such as KLF1 and BCL11A 5. Importantly,

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Comparative targeting analysis of KLF1, BCL11A, and HBG1/2 in CD34+ HSPCs by CRISPR/Cas9 for the induction of fetal hemoglobin

Lamsfus‐Calle

Daniel‐Moreno

Antony

et al. 2020

Sci Rep

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“…Several attempts have produced considerable trial evidence that HbF reactivation by gene interference of specific transcription regulators and factors could offer potential therapeutic support for β-hemoglobinopathies ( Zhou et al, 2010 ; Wilber et al, 2011 ; Antony et al, 2018 ). Both BCL11A and KLF1 are the main regulators engrossed in the process of γ- to β-globin shifting and the suppression of these genes leads to HbF rehabilitation ( Shariati et al, 2016 ).…”

Section: Enhancing the Safety And Fidelity Of The Crispr/cas9 Editing Toolsmentioning

confidence: 99%

The Potential of CRISPR/Cas9 Gene Editing as a Treatment Strategy for Inherited Diseases

Abdelnour

Xie

Hassanin

et al. 2021

Front. Cell Dev. Biol.

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Clustered regularly interspaced short palindromic repeats (CRISPR) is a promising innovative technology for genomic editing that offers scientists the chance to edit DNA structures and change gene function. It has several possible uses consisting of editing inherited deficiencies, treating, and reducing the spread of disorders. Recently, reports have demonstrated the creation of synthetic RNA molecules and supplying them alongside Cas9 into genome of eukaryotes, since distinct specific regions of the genome can be manipulated and targeted. The therapeutic potential of CRISPR/Cas9 technology is great, especially in gene therapy, in which a patient-specific mutation is genetically edited, or in the treating of human disorders that are untreatable with traditional treatments. This review focused on numerous, in vivo, in vitro, and ex vivo uses of the CRISPR/Cas9 technology in human inherited diseases, discovering the capability of this versatile in medicine and examining some of the main limitations for its upcoming use in patients. In addition to introducing a brief impression of the biology of the CRISPR/Cas9 scheme and its mechanisms, we presented the utmost recent progress in the uses of CRISPR/Cas9 technology in editing and treating of human genetic diseases.

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“…23 Despite off-target concerns, CRISPR-Cas9-based genome engineering has taken center stage in the field of gene therapy with promising curative potential for pathologies such as heart disease, 24 Duchenne muscular dystrophy, 25 sickle cell disease, and other bhemoglobinopathies. [26][27][28] In addition, base editing through CRISPR strategies enables single base pair changes (A-T to G-C and from C-G to T-A), opening new horizons for gene therapy. 29,30 Beyond advances to therapeutics, CRISPR-based gene drives have opened new doors, allowing scientists to circumvent the constraints of Mendelian inheritance.…”

Section: Introductionmentioning

confidence: 99%

Diversification of the CRISPR Toolbox: Applications of CRISPR-Cas Systems Beyond Genome Editing

et al. 2021

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The discovery of CRISPR has revolutionized the field of genome engineering, but the potential of this technology is far from reaching its limits. In this review, we explore the broad range of applications of CRISPR technology to highlight the rapid expansion of the field beyond gene editing alone. It has been demonstrated that CRISPR technology can control gene expression, spatiotemporally image the genome in vivo, and detect specific nucleic acid sequences for diagnostics. In addition, new technologies are under development to improve CRISPR quality controls for gene editing, thereby improving the reliability of these technologies for therapeutics and beyond. These are just some of the many CRISPR tools that have been developed in recent years, and the toolbox continues to diversify.

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CRISPR/Cas9 system: A promising technology for the treatment of inherited and neoplastic hematological diseases

Abstract: The ongoing advent of genome editing with programmable nucleases, including zinc-

Cited by 14 publications

References 86 publications

Comparative targeting analysis of KLF1, BCL11A, and HBG1/2 in CD34+ HSPCs by CRISPR/Cas9 for the induction of fetal hemoglobin

Comparative targeting analysis of KLF1, BCL11A, and HBG1/2 in CD34+ HSPCs by CRISPR/Cas9 for the induction of fetal hemoglobin

The Potential of CRISPR/Cas9 Gene Editing as a Treatment Strategy for Inherited Diseases

Diversification of the CRISPR Toolbox: Applications of CRISPR-Cas Systems Beyond Genome Editing

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