CRISPR/Cas-based gene editing in therapeutic strategies for beta-thalassemia

Zeng, Shujun; Lei, Shuangyin; Qu, Chao; Wang, Yue; Teng, Shuzhi; Huang, Ping

doi:10.1007/s00439-023-02610-9

Cited by 3 publications

(1 citation statement)

References 181 publications

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“… 277 Restoration of HbF expression has a positive therapeutic effect in most TDT patients compared with repair of the HBB gene. 292 Consistent with SCD, HPFH in β‐thalassemia likewise improves the clinical phenotype of patients and is a promising treatment for β‐thalassemia. 293 After disruption of the BCL11A binding site in the HBG1/HBG2 promoter, the introduction of the natural HPFH mutations ‐113A>G, ‐114C>T, ‐1175T>>C, ‐195C>G, and ‐198T>C into HSPC using CRISPR–Cas9/AAV6 significantly increased HbF expression.…”

Section: Gene Therapy In Human Diseasesmentioning

confidence: 98%

CRISPR technology in human diseases

Feng,

Li,

Zhou

et al. 2024

MedComm

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Gene editing is a growing gene engineering technique that allows accurate editing of a broad spectrum of gene‐regulated diseases to achieve curative treatment and also has the potential to be used as an adjunct to the conventional treatment of diseases. Gene editing technology, mainly based on clustered regularly interspaced palindromic repeats (CRISPR)–CRISPR‐associated protein systems, which is capable of generating genetic modifications in somatic cells, provides a promising new strategy for gene therapy for a wide range of human diseases. Currently, gene editing technology shows great application prospects in a variety of human diseases, not only in therapeutic potential but also in the construction of animal models of human diseases. This paper describes the application of gene editing technology in hematological diseases, solid tumors, immune disorders, ophthalmological diseases, and metabolic diseases; focuses on the therapeutic strategies of gene editing technology in sickle cell disease; provides an overview of the role of gene editing technology in the construction of animal models of human diseases; and discusses the limitations of gene editing technology in the treatment of diseases, which is intended to provide an important reference for the applications of gene editing technology in the human disease.

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Section: Gene Therapy In Human Diseasesmentioning

confidence: 98%

CRISPR technology in human diseases

Feng,

Li,

Zhou

et al. 2024

MedComm

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Regulatory Assessment of Casgevy for the Treatment of Transfusion-Dependent β-Thalassemia and Sickle Cell Disease with Recurrent Vaso-Occlusive Crises

Kerwash,

Sajic,

Rantell

et al. 2024

CIMB

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Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are hereditary haemoglobinopathies characterized by a reduction in functional β-globin chains. Both conditions cause tiredness and increase susceptibility to infection, which can lead organ failure, significantly reducing life expectancy and typically requiring those affected to undergo regular erythrocyte transfusion. Recently, a novel therapeutic treatment for SCD and TDT was approved by the UK regulatory body (Medicines and Healthcare products Regulatory Agency; MHRA). Exagamglogene autotemcel (Casgevy) is the first licensed therapy globally to utilize CRIPSR/Cas9 technology and induces an increase in expression of γ-globin chains to compensate for the reduction in functional β-globin. Casgevy represents a first-in-class therapeutic, and numerous considerations were made by the MHRA throughout its assessment of the medicine. These include, but are not limited to, the risk of tumorigenicity and off-target editing, a limited cohort size, the validity of proposed dosing and the conduction of only single-arm studies. The MHRA’s analyses of the data to support the proposed indications are presented and discussed throughout this manuscript. Overall, the sponsors claims were considered well supported by their data, and Casgevy was licensed for the treatment of TDT or SCD in patients 12 years of age and older for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen-matched related HSC donor is not available.

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Construction and Stability of All-in-One Adenovirus Vectors Simultaneously Expressing Four and Eight Multiplex Guide RNAs and Cas9 Nickase

Nakahara,

Tabata,

Kato

et al. 2024

IJMS

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CRISPR/Cas9 technology is expected to offer novel genome editing-related therapies for various diseases. We previously showed that an adenovirus vector (AdV) possessing eight expression units of multiplex guide RNAs (gRNAs) was obtained with no deletion of these units. Here, we attempted to construct “all-in-one” AdVs possessing expression units of four and eight gRNAs with Cas9 nickase, although we expected obstacles to obtain complete all-in-one AdVs. The first expected obstacle was that extremely high copies of viral genomes during replication may cause severe off-target cleavages of host cells and induce homologous recombination. However, surprisingly, four units in the all-in-one AdV genome were maintained completely intact. Second, for the all-in-one AdV containing eight gRNA units, we enlarged the E3 deletion in the vector backbone and shortened the U6 promoter of the gRNA expression units to shorten the AdV genome within the adenovirus packaging limits. The final size of the all-in-one AdV genome containing eight gRNA units still slightly exceeded the reported upper limit. Nevertheless, approximately one-third of the eight units remained intact, even upon preparation for in vivo experiments. Third, the genome editing efficiency unexpectedly decreased upon enlarging the E3 deletion. Our results suggested that complete all-in-one AdVs containing four gRNA units could be obtained if the problem of the low genome editing efficiency is solved, and those containing even eight gRNA units could be obtained if the obstacle of the vector size is also removed.

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CRISPR/Cas-based gene editing in therapeutic strategies for beta-thalassemia

Cited by 3 publications

References 181 publications

CRISPR technology in human diseases

CRISPR technology in human diseases

Regulatory Assessment of Casgevy for the Treatment of Transfusion-Dependent β-Thalassemia and Sickle Cell Disease with Recurrent Vaso-Occlusive Crises

Construction and Stability of All-in-One Adenovirus Vectors Simultaneously Expressing Four and Eight Multiplex Guide RNAs and Cas9 Nickase

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