Gene Editing-Based Technologies for Beta-hemoglobinopathies Treatment

Rahimmanesh, Ilnaz; Boshtam, Maryam; Kouhpayeh, Shirin; Khanahmad, Hossein; Dabiri, Arezou; Ahangarzadeh, Shahrzad; Esmaeili, Yasaman; Bidram, Elham; Vaseghi, Golnaz; Javanmard, Shaghayegh Haghjooy; Shariati, Laleh; Zarrabi, Ali; Varma, Rajender S.

doi:10.3390/biology11060862

Cited by 5 publications

(3 citation statements)

References 103 publications

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“…Genome editing (GE) can be considered among the most promising strategies to correct hereditary alterations in a variety of monogenic diseases, including hematopoietic pathologies [ 34 , 35 ]. Figure 2 depicts how CRISPR-Cas9 gene editing can be applied to β-thalassemia [ 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. CRISPR-Cas9 gene editing can be proposed for efficient correction of the NM_000518.5:c.118C>T thalassemia variant (HGVS nomenclature, β 0 39C>T traditional nomenclature) [ 45 ].…”

Section: The Impact Of Changes In the Expression Of Alpha-globin Gene...mentioning

confidence: 99%

Impact of α-Globin Gene Expression and α-Globin Modifiers on the Phenotype of β-Thalassemia and Other Hemoglobinopathies: Implications for Patient Management

Traeger-Synodinos,

Vrettou,

Sofocleous

et al. 2024

IJMS

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In this short review, we presented and discussed studies on the expression of globin genes in β-thalassemia, focusing on the impact of α-globin gene expression and α-globin modifiers on the phenotype and clinical severity of β-thalassemia. We first discussed the impact of the excess of free α-globin on the phenotype of β-thalassemia. We then reviewed studies focusing on the expression of α-globin-stabilizing protein (AHSP), as a potential strategy of counteracting the effects of the excess of free α-globin on erythroid cells. Alternative processes controlling α-globin excess were also considered, including the activation of autophagy by β-thalassemia erythroid cells. Altogether, the studies reviewed herein are expected to have a potential impact on the management of patients with β-thalassemia and other hemoglobinopathies for which reduction in α-globin excess is clinically beneficial.

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Section: The Impact Of Changes In the Expression Of Alpha-globin Gene...mentioning

confidence: 99%

Impact of α-Globin Gene Expression and α-Globin Modifiers on the Phenotype of β-Thalassemia and Other Hemoglobinopathies: Implications for Patient Management

Traeger-Synodinos,

Vrettou,

Sofocleous

et al. 2024

IJMS

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“…Single-mutation diseases such as SCD, represent ideal targets for gene editing. Moreover, the ability of gene editing to introduce targeted mutations that may cause a disease-modulatory effect made it possible to use a universal approach to target, in addition to SCD, the many different thalassemia mutations through the reactivation of the endogenous γ-globin gene [25][26][27][28][29][30][31][32]. Gene editing utilizes for the targeted introduction of point mutations or small deletions and insertions of the cells' endogenous DNA damage response mechanism.…”

Section: Introductionmentioning

confidence: 99%

Precision Editing as a Therapeutic Approach for β-Hemoglobinopathies

Paschoudi

Yannaki

Psatha

2023

IJMS

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Beta-hemoglobinopathies are the most common genetic disorders worldwide, caused by a wide spectrum of mutations in the β-globin locus, and associated with morbidity and early mortality in case of patient non-adherence to supportive treatment. Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) used to be the only curative option, although the indispensable need for an HLA-matched donor markedly restricted its universal application. The evolution of gene therapy approaches made possible the ex vivo delivery of a therapeutic β- or γ- globin gene into patient-derived hematopoietic stem cells followed by the transplantation of corrected cells into myeloablated patients, having led to high rates of transfusion independence (thalassemia) or complete resolution of painful crises (sickle cell disease-SCD). Hereditary persistence of fetal hemoglobin (HPFH), a syndrome characterized by increased γ-globin levels, when co-inherited with β-thalassemia or SCD, converts hemoglobinopathies to a benign condition with mild clinical phenotype. The rapid development of precise genome editing tools (ZFN, TALENs, CRISPR/Cas9) over the last decade has allowed the targeted introduction of mutations, resulting in disease-modifying outcomes. In this context, genome editing tools have successfully been used for the introduction of HPFH-like mutations both in HBG1/HBG2 promoters or/and in the erythroid enhancer of BCL11A to increase HbF expression as an alternative curative approach for β-hemoglobinopathies. The current investigation of new HbF modulators, such as ZBTB7A, KLF-1, SOX6, and ZNF410, further expands the range of possible genome editing targets. Importantly, genome editing approaches have recently reached clinical translation in trials investigating HbF reactivation in both SCD and thalassemic patients. Showing promising outcomes, these approaches are yet to be confirmed in long-term follow-up studies.

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“…Fortunately, recent research found that disrupting the GATAA motif in the BCL11A erythroid enhancer resulted in a significant increase in HbF expression 9 . Fortunately, recent studies revealed that the disruption of the GATAA motif in BCL11A erythroid enhancer led to a substantial increase in HbF expression 10 .…”

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9 Ablated BCL11A Unveils the Genes with Possible Role of Globin Switching

Motlagh¹,

Soleimanpour‐Lichaei²,

Shamsara³

et al. 2023

Adv Pharm Bull

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Purpose: HbF upregulation is a mitigating factor in β-hemoglobinopathies therapy like β-thalassemia and sickle cell diseases. Finding molecular mechanisms and the key regulators responsible for globin switching could be helpful to develop effective ways to HbF upregulation. In our paper published recently, we introduced certain factors probably responsible for globin switching using in-silico study. The aim of this paper is experimental confirmation of the factors. Methods: We stablished K562 cell line with BCL11A knock down leading to increase in HBG1/2 using CRISPR/Cas9 system. After that, we determined the expression of factors introduced in previous paper by qPCR. Results: Results showed that BCL11A was substantially downregulated and HBG1/2 was upregulated in transfected K562 cells. Also, the experimental and bioinformatics data were consistent with each other for three genes, HIST1H2BL، TRIM58، AL13243.2. These data Conclusion: BCL11A is a good candidate for the treatment of β-hemoglobinopathies, with high HbF reactivation. In addition, HIST1H2BL, TRIM58 and AL13243.2 probably play a key role in the mechanism of hemoglobin switching. To further validate the selected genes, more experimental in-vivo and in-vitro studies are required.

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Gene Editing-Based Technologies for Beta-hemoglobinopathies Treatment

Cited by 5 publications

References 103 publications

Impact of α-Globin Gene Expression and α-Globin Modifiers on the Phenotype of β-Thalassemia and Other Hemoglobinopathies: Implications for Patient Management

Impact of α-Globin Gene Expression and α-Globin Modifiers on the Phenotype of β-Thalassemia and Other Hemoglobinopathies: Implications for Patient Management

Precision Editing as a Therapeutic Approach for β-Hemoglobinopathies

CRISPR/Cas9 Ablated BCL11A Unveils the Genes with Possible Role of Globin Switching

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