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Review
. 2023 Nov 2:11:1249275.
doi: 10.3389/fped.2023.1249275. eCollection 2023.

Genome editing for sickle cell disease: still time to correct?

Giulia Ceglie #  1   2 , Marco Lecis #  1   2   3 , Gabriele Canciani  1   4 , Mattia Algeri  1 , Giacomo Frati  1
Affiliations
Review

Genome editing for sickle cell disease: still time to correct?

Giulia Ceglie et al. Front Pediatr. .

Abstract

Sickle cell disease (SCD) is an inherited blood disorder, due to a single point mutation in the β-globin gene (HBB) leading to multisystemic manifestations and it affects millions of people worldwide. The monogenic nature of the disease and the availability of autologous hematopoietic stem cells (HSCs) make this disorder an ideal candidate for gene modification strategies. Notably, significant advances in the field of gene therapy and genome editing that took place in the last decade enabled the possibility to develop several strategies for the treatment of SCD. These curative approaches were firstly based on the correction of disease-causing mutations holding the promise for a specific, effective and safe option for patients. Specifically, gene-editing approaches exploiting the homology directed repair pathway were investigated, but soon their limited efficacy in quiescent HSC has curbed their wider development. On the other hand, a number of studies on globin gene regulation, led to the development of several genome editing strategies based on the reactivation of the fetal γ-globin gene (HBG) by nuclease-mediated targeting of HBG-repressor elements. Although the efficiency of these strategies seems to be confirmed in preclinical and clinical studies, very little is known about the long-term consequences of these modifications. Moreover, the potential genotoxicity of these nuclease-based strategies must be taken into account, especially when associated with high targeting rates. The recent introduction of nuclease-free genome editing technologies brought along the potential for safer strategies for SCD gene correction, which may also harbor significant advantages over HBG-reactivating ones. In this Review, we discuss the recent advances in genome editing strategies for the correction of SCD-causing mutations trying to recapitulate the promising strategies currently available and their relative strengths and weaknesses.

Keywords: CRISPR/Cas9; fetal hemoglobin reactivation; gene editing; gene therapy; globin genes regulation; sickle cell disease.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Gene therapy/editing for SCD. The ex vivo gene therapy relies upon isolation of patients HSPCs, their manipulation and subsequent infusion of the cellular product after a conditioning regimen. The most exploited strategies for this scope are: ex vivo gene addition based on virus-mediated delivery of a functional copy of HBB gene (e.g. lentiglobin); ex vivo genome editing (nuclease based HDR-mediated correction of the HBB gene); ex vivo gene editing (nuclease based NHEJ-mediated HbF induction) The in vivo gene therapy relies upon direct infusion of the editing machinery to target patient resident HSPCs, without isolation-manipulation-conditioning and re-infusion. (Created with BioRender.com).
Figure 2
Figure 2
CRISPR/Cas9 genome editing approaches for SCD. (1) The HDR-mediated Gene Correction of the disease-causing mutation, using a DNA Template, leading to HbA restoration. (2) NHEJ-mediated Gene Disruption of target sequences, leading to HbF induction. Different strategies aimed to this goal: a. Large deletions that could either eliminate HbF inhibitory sequences or juxtapose the γ-globin promoters to remote enhancer regions; b. Targeting the HBG1/2 promoters for the disruption of binding sites for γ-globin transcriptional repressors; c. Disruption of the GATA1 motif in the erythroid-specific intronic enhancer of BCL11A, resulting in BCL11A knock down. Recently established CRISPR/Cas9-derived editing platforms, i.e. Base editors (3) and Prime editors (4), has been tested to directly change the HbS into a non-sickling variant (Hb Makassar), or to restore the correct HbA protein. (Created with BioRender.com).
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Grants and funding

This work was supported also by the Italian ministry of health with “current research” fund.

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