Abstract
Hemoglobin is a tetrameric protein composed of two α and two β chains, each containing a heme group that reversibly binds oxygen. The composition of hemoglobin changes during development in order to fulfill the need of the growing organism, stably maintaining a balanced production of α-like and β-like chains in a 1:1 ratio. Adult hemoglobin (HbA) is composed of two α and two β subunits (α2β2 tetramer), whereas fetal hemoglobin (HbF) is composed of two γ and two α subunits (α2γ2 tetramer). Qualitative or quantitative defects in β-globin production cause two of the most common monogenic-inherited disorders: β-thalassemia and sickle cell disease. The high frequency of these diseases and the relative accessibility of hematopoietic stem cells make them an ideal candidate for therapeutic interventions based on genome editing. These strategies move in two directions: the correction of the disease-causing mutation and the reactivation of the expression of HbF in adult cells, in the attempt to recreate the effect of hereditary persistence of fetal hemoglobin (HPFH) natural mutations, which mitigate the severity of β-hemoglobinopathies. Both lines of research rely on the knowledge gained so far on the regulatory mechanisms controlling the differential expression of globin genes during development.
Highlights
Because of the abundance and accessibility of red blood cells, globins served as a model for major discoveries later extended to other genes
The number of genome-editing tools is rapidly increasing (Papasavva et al, 2019; Doudna, 2020), holding the promise to reach in the near future a safe, precise, and efficient editing of β-disease mutations, via different strategies
The availability of different molecular options (HDR, non-homologous end joining (NHEJ), and base editors (BEs) based, Figure 1) poses the problem of the evaluation of the pros and cons of each strategy (Ikawa et al, 2019; Papasavva et al, 2019): homology-directed repair (HDR)-based approaches could ensure a higher precision at the expenses of hematopoietic stem cells (HSCs) correction efficiency, whereas NHEJ is more efficient but less precise
Summary
Because of the abundance and accessibility of red blood cells, globins served as a model for major discoveries later extended to other genes. The “perfect” editing should leave no trace, to avoid unintended off-target mutations and should at the same time guarantee high editing efficiency with reduced toxicity for HSCs. To reach this goal, an intense optimization work has been focused on the different steps of the genome editing procedure: the development of new editing reagents [single-strand DNA donor templates (Park et al, 2019), modified sgRNA (De Ravin et al, 2017; Park et al, 2019), pre-complexed ribonucleoproteins (RNPs) (Gundry et al, 2016)] and their integration in improved platforms for their delivery (Lino et al, 2018; Lattanzi et al, 2019; Schiroli et al, 2019).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
