International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 193-202 http://medscipublisher.com/index.php/ijmms 198 in successful engraftment in a mouse model and the production of normal hemoglobin, indicating potential clinical benefits (Ikawa et al., 2019; Newby et al., 2021). Another case study involved the use of a custom adenine base editor (ABE8e-NRCH) to convert the SCD allele into a non-pathogenic variant, resulting in significant reduction of hypoxia-induced sickling and near-normal hematological parameters in mice (Cisneros and Thein, 2020). A study on the use of base editing to upregulate fetal hemoglobin (HbF) in CD34+ HSPCs showed that editing at key regulatory motifs within the HBG1 and HBG2 promoters resulted in significant increases in HbF levels, providing protection to the majority of SCA patients (Moran et al., 2018). These case studies underscore the transformative potential of gene editing technologies in providing a curative treatment for SCA (Figure 4) (Cisneros and Thein, 2020). The ongoing clinical trials and case studies highlight the significant advancements in gene editing technologies for the treatment of sickle cell anemia. These approaches offer promising prospects for providing a universal curative option for patients with SCA, with ongoing research and clinical trials continuing to refine and optimize these treatments (DeWitt et al., 2016; Moran et al., 2018; Lin et al., 2019; Cisneros and Thein, 2020; Newby et al., 2021; Hanna et al., 2023; Zarghamian et al., 2023). Figure 4 Schematic pathophysiology review of sickle cell disease and its main different targets for intervention (Adopted from Cisneros and Thein, 2020) Image caption: This image provides a schematic review of the pathophysiology of sickle cell disease (SCD) and outlines different targets for intervention (Adopted from Cisneros and Thein, 2020) 6 Challenges and Barriers to Implementation 6.1 Technical challenges Gene editing technologies, particularly CRISPR-Cas9, have shown promise in treating sickle cell anemia (SCA) by targeting specific genetic mutations. However, several technical challenges remain. One significant issue is the efficiency and specificity of gene modification. Achieving high editing efficiency without off-target effects is crucial for clinical success (Lin et al., 2017; Ikawa et al., 2019; Frangoul et al., 2020). Additionally, the delivery of gene-editing tools to hematopoietic stem cells (HSCs) and ensuring their robust and non-toxic engraftment pose significant hurdles (Rosanwo and Bauer, 2021). The optimization of these processes is essential to maximize therapeutic benefits while minimizing potential risks (Ebens et al., 2019; Lin et al., 2019). 6.2 Ethical and regulatory issues The ethical implications of gene editing are profound, particularly concerning germline modifications that could be inherited by future generations. While current therapies focus on somatic cells, the potential for germline editing raises concerns about unintended consequences and long-term effects (Romero et al., 2018; Rahimmanesh et al., 2022). Regulatory frameworks must evolve to address these ethical considerations, ensuring that gene editing technologies are applied responsibly and ethically. Moreover, the approval process for new gene therapies is complex and requires rigorous evaluation to ensure safety and efficacy (Urnov, 2017). 6.3 Socioeconomic barriers The high cost of gene editing therapies presents a significant barrier to widespread implementation. Current ex vivo HSC gene therapy platforms are expensive, limiting access to treatment, especially in regions where SCA is most prevalent (Lin et al., 2019). Ensuring equitable access to these advanced therapies requires addressing the
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