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

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 (HS...

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Autores principales: Ceglie, Giulia, Lecis, Marco, Canciani, Gabriele, Algeri, Mattia, Frati, Giacomo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10652763/
https://www.ncbi.nlm.nih.gov/pubmed/38027257
http://dx.doi.org/10.3389/fped.2023.1249275
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author Ceglie, Giulia
Lecis, Marco
Canciani, Gabriele
Algeri, Mattia
Frati, Giacomo
author_facet Ceglie, Giulia
Lecis, Marco
Canciani, Gabriele
Algeri, Mattia
Frati, Giacomo
author_sort Ceglie, Giulia
collection PubMed
description 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.
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spelling pubmed-106527632023-11-02 Genome editing for sickle cell disease: still time to correct? Ceglie, Giulia Lecis, Marco Canciani, Gabriele Algeri, Mattia Frati, Giacomo Front Pediatr Pediatrics 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. Frontiers Media S.A. 2023-11-02 /pmc/articles/PMC10652763/ /pubmed/38027257 http://dx.doi.org/10.3389/fped.2023.1249275 Text en © 2023 Ceglie, Lecis, Canciani, Algeri and Frati. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (https://creativecommons.org/licenses/by/4.0/) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pediatrics
Ceglie, Giulia
Lecis, Marco
Canciani, Gabriele
Algeri, Mattia
Frati, Giacomo
Genome editing for sickle cell disease: still time to correct?
title Genome editing for sickle cell disease: still time to correct?
title_full Genome editing for sickle cell disease: still time to correct?
title_fullStr Genome editing for sickle cell disease: still time to correct?
title_full_unstemmed Genome editing for sickle cell disease: still time to correct?
title_short Genome editing for sickle cell disease: still time to correct?
title_sort genome editing for sickle cell disease: still time to correct?
topic Pediatrics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10652763/
https://www.ncbi.nlm.nih.gov/pubmed/38027257
http://dx.doi.org/10.3389/fped.2023.1249275
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