International Journal of Molecular Medical Science, 2024, Vol.14, No.3, 193-202 http://medscipublisher.com/index.php/ijmms 193 Review and Progress Open Access Prospects of Gene Editing Technologies in Sickle Cell Anemia Qiyan Lou, Xiaoying Xu Biotechnology Research Center, Cuixi Academy of Biotechnology, Zhuji, 311800, Zhejiang, China Corresponding author: xiaoying.xu@cuixi.org International Journal of Molecular Medical Science, 2024, Vol.14, No.3 doi: 10.5376/ijmms.2024.14.0022 Received: 18 May., 2024 Accepted: 20 Jun., 2024 Published: 30 Jun., 2024 Copyright © 2024 Lou and Xu, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Lou Q.Y., and Xu X.Y., 2024, Prospects of gene editing technologies in sickle cell Anemia, International Journal of Molecular Medical Science, 14(3): 193-202 (doi: 10.5376/ijmms.2024.14.0022) Abstract Sickle cell anemia (SCA) is a severe monogenic disorder characterized by the presence of abnormal hemoglobin, leading to various clinical complications. Recent advancements in gene editing technologies, particularly CRISPR/Cas9, have shown promising potential in treating SCA by targeting and modifying specific genetic loci to upregulate fetal hemoglobin (HbF) or correct the sickle mutation. This study explores the prospects of gene editing technologies in the treatment of SCA, focusing on the efficacy, safety, and durability of these approaches. Studies have demonstrated that CRISPR/Cas9 can efficiently edit hematopoietic stem and progenitor cells (HSPCs) to recreate genetic variants associated with elevated HbF, resulting in significant therapeutic benefits. Additionally, various delivery methods for CRISPR/Cas9, including ribonucleoprotein complexes and lentiviral vectors, have been optimized to balance efficiency and cytotoxicity. Clinical trials and preclinical studies have shown that gene-edited cells can engraft and persist in vivo, maintaining therapeutic benefits over extended periods. Despite these advancements, challenges such as off-target effects and the need for improved targeting methods remain. This study provides a comprehensive overview of the current state of gene editing technologies in SCA treatment, highlighting key findings and future directions. Keywords Sickle cell anemia; CRISPR/Cas9; Fetal hemoglobin; Gene editing; Hematopoietic stem cells 1 Introduction Sickle Cell Anemia (SCA) is a debilitating hereditary blood disorder that affects millions of individuals worldwide. The advent of gene editing technologies has opened new avenues for potential curative treatments for this condition. Sickle Cell Anemia is caused by a single-point mutation in the β-globin gene (HBB), leading to the production of abnormal hemoglobin S (HbS) (DeWitt et al., 2016; Romero et al., 2018). This mutation results in the deformation of red blood cells into a sickle shape, causing vaso-occlusion, severe pain, and progressive organ damage (DeWitt et al., 2016; Park et al., 2019). The disease is most prevalent in regions where malaria is endemic, as the sickle cell trait provides some protection against malaria (Romero et al., 2018). Current treatments, such as hydroxyurea and blood transfusions, provide symptomatic relief but do not offer a cure. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option available, but it is limited by donor availability and the risk of graft-versus-host disease (Park et al., 2019; Zarghamian et al., 2023). Gene editing technologies, particularly CRISPR/Cas9, base editors, and homology-directed repair (HDR), have shown promising results in correcting the genetic mutation responsible for SCA (Hossain and Bungert, 2017; Newby et al., 2021; Rosanwo and Bauer, 2021). CRISPR/Cas9 has been used to disrupt regulatory elements that inhibit fetal hemoglobin (HbF) production, thereby compensating for defective adult hemoglobin (Rosanwo and Bauer, 2021; Zarghamian et al., 2023). Base editors, such as adenine base editors (ABE), have been employed to convert the sickle cell allele into a non-pathogenic variant, showing durable gene editing in preclinical models (Zeng et al., 2020; Newby et al., 2021). These technologies offer the potential for a one-time, autologous treatment that could eliminate the pathogenic HbS and generate benign hemoglobin variants (Newby et al., 2021; Germino-Watnick et al., 2022). The study is to provide a comprehensive overview of the current advancements in gene editing technologies for the treatment of Sickle Cell Anemia. We discuss the various strategies employed, their efficacy and safety profiles, and the challenges that need to be addressed for clinical translation. By synthesizing findings from recent studies, this study seeks to highlight the transformative potential of gene editing as a universal curative option for SCA.
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