International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 193-202 http://medscipublisher.com/index.php/ijmms 197 improved erythropoiesis and reduced sickling in vivo (Bak et al., 2018; Wilkinson et al., 2021). Gene editing technologies have shown significant potential in correcting the HBB mutation and improving the phenotype and survival rates in animal models of SCA. These preclinical successes pave the way for future clinical trials and the potential for curative therapies for patients with sickle cell anemia. 5 Clinical Trials and Advances 5.1 Current clinical trials Recent advancements in gene editing technologies have paved the way for promising clinical trials aimed at treating sickle cell anemia (SCA). One notable approach involves the use of viral transduction to introduce anti-sickling β-like globin genes into hematopoietic stem/progenitor cells (HSPCs). Early-phase clinical studies have shown promising preliminary results, indicating the potential of this method to provide a curative treatment for SCA (Zarghamian et al., 2023). Another significant development is the use of CRISPR-Cas nucleases and base editors to reactivate γ-globin expression, which can replace the faulty β-globin chain. This approach has demonstrated efficacy in both preclinical animal models and clinical trials, showing promising results in terms of safety and effectiveness (Lin et al., 2019). Additionally, the use of zinc finger nucleases (ZFNs) to disrupt the BCL11A erythroid enhancer has been shown to increase fetal hemoglobin (HbF) levels in patients with SCA, with ongoing phase 1/2a clinical trials further evaluating this method (DeWitt et al., 2016; Rosanwo and Bauer, 2021) (Figure 3). Moreover, the investigational gene-edited autologous hematopoietic stem cell medicine, EDIT-301, which employs AsCas12a to edit the HBG1/2 promoters, has shown rapid and sustained normalization of hemoglobin levels and increased HbF production in patients with severe SCA and transfusion-dependent beta-thalassemia (TDT). These clinical trials highlight the potential of gene editing technologies to provide a curative treatment for SCA (Figure 3) (Rahimmanesh et al., 2022). Figure 3 Molecular mechanism of β-globin repair in beta-hemoglobinopathies patients by genome editing tools (Adopted from Rahimmanesh et al., 2022) Image caption: This figure illustrates the molecular mechanisms involved in β-globin repair in beta-hemoglobinopathy patients using genome editing tools (Adopted from Rahimmanesh et al., 2022) 5.2 Case studies Several case studies have demonstrated the potential of gene editing technologies in treating SCA, For instance, a study by DeWitt et al. (2016) utilized CRISPR/Cas9 to edit hematopoietic stem cells from SCA patients, resulting
RkJQdWJsaXNoZXIy MjQ4ODYzNQ==