The efficacy of CRISPR/Cas۹ system in modifying hematopoietic stem cells in β-hemoglobinopathies

Background and objective Allogenic hematopoietic stem cell transplantation (HSCT) has been used for β- hemoglobinopathies such as Sickle cell disease (SCD) and β-thalassemia for many years. However, it has some limitations such as lack of a suitable donor, graft-versus-host disease (GVHD) and infectious complications. Modification of HSC by viral vectors such as gamma-retroviral vectors has the risk of activation of proto-oncogenes in some recipients. CRISPR/cas۹ system is a good tool in order to modify the target genes. This system edits genes by precisely cutting DNA and then letting natural DNA repair. Therefore, the CRISPR/Cas۹-edited autologous HSCs would be helpful to modify target genes in a way to lead β-hemoglobinopathies improvement. This study aims to demonstrate the effectiveness of CRISPR/cas۹ in hematopoietic stem cell transplantation in β-hemoglobinopathies. Search Methods A total of ۳۰ pre-clinical studies related to CRISPR/cas۹ published from ۱۷ November ۲۰۱۶ till ۲ July ۲۰۲۱ was conducted using MEDLINE and SCOPUS. Findings CRISPR/cas۹ can be used for three modifying process such as gene addition, gene disruption and gene correction that the last one was used more in pre-clinical studies of the SCD and β-thalassemia in CD۳۴+ induced pluripotent stem cells. Some studies were focused on the naturally occurring hereditary persistence of fetal hemoglobin (HPFH) by reactivation of fetal γ-globin or by deleting the δ-globin and β-globin genes by CRISPR/Cas۹ editing. Some studies also used CRISPR-Cas۹ in editing the epigenetic factors such as NuRD complex and DNA methyltransferase ۱ (DNMT۱) which affect γ-globin expression to induce HbF for the treatment of SCD. Extreme HbF induction was done by the inhibition of histone lysine methyltransferase in human adult erythroid cells. Currently, there are also nine clinical trials in recruiting and not recruiting stage which utilize CRISPR/Cas۹ technology to modify autologous HSCs to treat β-thalassemia and SCD (https://clinicaltrials.gov). Conclusion Given that there are some potential risks of CRISPR/Cas۹-mediated off-target mutations, the future perspective of CRISPR/Cas۹-mediated autologous HSCT seems very bright and this system would be considered as a therapeutic tool for β-hemoglobinopathies all over the world.

کلیدواژه ها:

CRISPR/Cas۹ ، Hematopoietic stem cell transplantation (HSCT) ، β-hemoglobinopathy