Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies

Venkatesan, Vigneshwaran; Christopher, Abisha Crystal; Rhiel, Manuel; Azhagiri, Manoj Kumar K; Babu, Prathibha; Walavalkar, Kaivalya; Saravanan, Bharath; Andrieux, Geoffroy; Rangaraj, Sumathi; Srinivasan, Saranya; Karuppusamy, Karthik V.; Jacob, Abraham; Bagchi, Abhirup; Pai, Aswin Anand; Nakamura, Yukio; Kurita, Ryo; Balasubramanian, Poonkuzhali; Pai, Rekha; Marepally, Srujan; Mohankumar, Kumarasamypet M.; Velayudhan, Shaji R; Boerries, Melanie; Notani, Dimple; Cathomen, Toni; Srivastava, Alok; Thangavel, Saravanabhavan

doi:10.1016/j.omtn.2023.04.024

Cited by 8 publications

(8 citation statements)

References 54 publications

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“…The development of mobilization-based chemotherapy-free HSPC transplantation and concomitant overexpression of homing/engraftment enhancers for early engraftment is expected to improve the success rates of HSPC gene editing ( Felker et al, 2022 ; Omer-Javed et al, 2022 ). The ex vivo culture-free HSPC gene editing and gene editing of a sub-population of HSPCs can potentially simplify the gene therapy approach ( Radtke et al, 2020 ; Karuppusamy et al, 2022 ; Venkatesan et al, 2023 ). Gene editing delivery tools have played a substantial role in the success of HSPC gene editing; however, they are also a cause of the high cost of HSPC gene therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Electroporation is the most effective method for delivering mRNA and protein with high efficiency ( Vakulskas et al, 2018 ; Yudovich et al, 2020 ). In addition, this approach permits multiplex gene editing by delivering RNPs/mRNA to edit different target loci simultaneously ( Bak et al, 2017 ; Zeng et al, 2020 ; Venkatesan et al, 2023 ). HDR gene editing requires donor DNA co-delivery with a nuclease and sgRNAs.…”

Section: Introductionmentioning

confidence: 99%

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Current approaches and potential challenges in the delivery of gene editing cargos into hematopoietic stem and progenitor cells

Murugesan,

Karuppusamy,

Marepally

et al. 2023

Front. Genome Ed.

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Advancements in gene delivery and editing have expanded the applications of autologous hematopoietic stem and progenitor cells (HSPCs) for the treatment of monogenic and acquired diseases. The gene editing toolbox is growing, and the ability to achieve gene editing with mRNA or protein delivered intracellularly by vehicles, such as electroporation and nanoparticles, has highlighted the potential of gene editing in HSPCs. Ongoing phase I/II clinical trials with gene-edited HSPCs for β-hemoglobinopathies provide hope for treating monogenic diseases. The development of safe and efficient gene editing reagents and their delivery into hard-to-transfect HSPCs have been critical drivers in the rapid translation of HSPC gene editing into clinical studies. This review article summarizes the available payloads and delivery vehicles for gene editing HSPCs and their potential impact on therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Current approaches and potential challenges in the delivery of gene editing cargos into hematopoietic stem and progenitor cells

Murugesan,

Karuppusamy,

Marepally

et al. 2023

Front. Genome Ed.

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“…In addition, GWAS-identified single nucleotide polymorphisms (SNPs) have been mapped within the erythroid enhancer of the BCL11A gene [84]. This was a key contribution to the development of the pharmacogenomics of β-thalassemia, especially after the development of gene editing protocols that were able to demonstrate that the disruption of discrete portions of the BCL11A enhancer are associated with a reduction in the expression of BCL11A and an increase in γ-globin gene expression and HbF production [90][91][92]. More recently, Antoniou et al have used base editing to generate a large variety of mutations within the −200 region of the γ-globin gene promoters [91].…”

Section: The Search Of Dna Polymorphisms Associated With High Express...mentioning

confidence: 99%

“…For instance, Roy et al studied the influence of BCL11A, HBS1L-MYB, and HBBP1 single nucleotide polymorphisms (in addition to the HBG2 XmnI polymorphism) on the levels of endogenous production of HbF and found a significant association of HbF levels with rs2071348 (BCL11A) and rs4895441 (HBS1L-MYB), respectively. The HBG2 XmnI polymorphism showed the strongest association [76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95]. An extensive description of SNPs associated with high production of HbF is outside the objectives of the present review that is mainly focused on the most relevant (in our opinion) DNA polymorphisms considered in published pharmacogenomic studies on β-thalassemia and SCD.…”

Section: Major Dna Polymorphisms Associated With High Expression Of γ...mentioning

confidence: 99%

Pharmacogenomics of Drugs Used in β-Thalassemia and Sickle-Cell Disease: From Basic Research to Clinical Applications

Gambari,

Waziri,

Goonasekera

et al. 2024

IJMS

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In this short review we have presented and discussed studies on pharmacogenomics (also termed pharmacogenetics) of the drugs employed in the treatment of β-thalassemia or Sickle-cell disease (SCD). This field of investigation is relevant, since it is expected to help clinicians select the appropriate drug and the correct dosage for each patient. We first discussed the search for DNA polymorphisms associated with a high expression of γ-globin genes and identified this using GWAS studies and CRISPR-based gene editing approaches. We then presented validated DNA polymorphisms associated with a high HbF production (including, but not limited to the HBG2 XmnI polymorphism and those related to the BCL11A, MYB, KLF-1, and LYAR genes). The expression of microRNAs involved in the regulation of γ-globin genes was also presented in the context of pharmacomiRNomics. Then, the pharmacogenomics of validated fetal hemoglobin inducers (hydroxyurea, butyrate and butyrate analogues, thalidomide, and sirolimus), of iron chelators, and of analgesics in the pain management of SCD patients were considered. Finally, we discuss current clinical trials, as well as international research networks focusing on clinical issues related to pharmacogenomics in hematological diseases.

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“…For instance, Ye et al (2016) proposed genome editing using CRISPR-Cas9 to create an HPFH genotype in hematopoietic stem/progenitor cells (HSPCs), obtaining an increase of expression of γ-globin genes. In fact, these gene edited regions were known (or were hypothesized) to contain putative fetal hemoglobin (HbF) silencers, as also pro-posed by Antoniani et al (2018) and more recently by Venkatesan et al (2023a) .…”

Section: Crispr-cas9 Based Approaches To Reactivate γ-Globin Gene Exp...mentioning

confidence: 99%

Combined approaches for increasing fetal hemoglobin (HbF) and de novo production of adult hemoglobin (HbA) in erythroid cells from β-thalassemia patients: treatment with HbF inducers and CRISPR-Cas9 based genome editing

Finotti

Gambari

2023

Front. Genome Ed.

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Genome editing (GE) is one of the most efficient and useful molecular approaches to correct the effects of gene mutations in hereditary monogenetic diseases, including β-thalassemia. CRISPR-Cas9 gene editing has been proposed for effective correction of the β-thalassemia mutation, obtaining high-level “de novo” production of adult hemoglobin (HbA). In addition to the correction of the primary gene mutations causing β-thalassemia, several reports demonstrate that gene editing can be employed to increase fetal hemoglobin (HbF), obtaining important clinical benefits in treated β-thalassemia patients. This important objective can be achieved through CRISPR-Cas9 disruption of genes encoding transcriptional repressors of γ-globin gene expression (such as BCL11A, SOX6, KLF-1) or their binding sites in the HBG promoter, mimicking non-deletional and deletional HPFH mutations. These two approaches (β-globin gene correction and genome editing of the genes encoding repressors of γ-globin gene transcription) can be, at least in theory, combined. However, since multiplex CRISPR-Cas9 gene editing is associated with documented evidence concerning possible genotoxicity, this review is focused on the possibility to combine pharmacologically-mediated HbF induction protocols with the “de novo” production of HbA using CRISPR-Cas9 gene editing.

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Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies

Cited by 8 publications

References 54 publications

Current approaches and potential challenges in the delivery of gene editing cargos into hematopoietic stem and progenitor cells

Current approaches and potential challenges in the delivery of gene editing cargos into hematopoietic stem and progenitor cells

Pharmacogenomics of Drugs Used in β-Thalassemia and Sickle-Cell Disease: From Basic Research to Clinical Applications

Combined approaches for increasing fetal hemoglobin (HbF) and de novo production of adult hemoglobin (HbA) in erythroid cells from β-thalassemia patients: treatment with HbF inducers and CRISPR-Cas9 based genome editing

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