International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 209 microRNAs (miRNAs), long non-coding RNAs (lncRNAs), piwi-interacting RNAs (piRNAs), and others. They are involved in processes such as chromatin remodeling, DNA methylation, and histone modification, which are essential for maintaining cellular function and identity (Zhou et al., 2010; Peschansky and Wahlestedt, 2014; Wei et al., 2014). The majority of human transcripts are non-coding, highlighting their significant role in the regulation of gene expression (Zhou et al., 2010). 7.2 miRNAs in sickle cell anemia (SCA) MicroRNAs (miRNAs) are small ncRNAs that typically function by binding to complementary sequences on target mRNAs, leading to their degradation or translational repression. In the context of Sickle Cell Anemia (SCA), miRNAs have been shown to influence the expression of genes involved in erythropoiesis and hemoglobin switching. Dysregulation of specific miRNAs can contribute to the pathophysiology of SCA by affecting the balance between fetal and adult hemoglobin, thus impacting the severity of the disease (Wei et al., 2014; Pathania et al., 2021). For instance, certain miRNAs may target transcription factors or other regulatory proteins that are crucial for the expression of fetal hemoglobin, which has been shown to ameliorate the symptoms of SCA. 7.3 Therapeutic potential of non-coding RNAs The therapeutic potential of ncRNAs in SCA is a promising area of research. Given their regulatory roles, ncRNAs can be targeted to modulate gene expression and epigenetic states beneficially. For example, miRNA mimics or inhibitors can be designed to restore normal gene expression patterns disrupted in SCA. Similarly, lncRNAs, which can act as scaffolds for chromatin-modifying complexes or decoys for miRNAs, offer another layer of therapeutic intervention (Forrest and Khalil, 2017; Zhang et al., 2020; Tachiwana and Saitoh, 2021). The ability to modulate ncRNA activity opens up new avenues for developing treatments that can potentially correct the underlying genetic and epigenetic abnormalities in SCA (Peschansky and Wahlestedt, 2014; Huang et al., 2020). 8 Current and Emerging Epigenetic Therapies for Sickle Cell Anemia 8.1 Histone deacetylase inhibitors (HDACis) Histone deacetylase inhibitors (HDACis) have shown promise in the treatment of various diseases, including cancer and potentially sickle cell anemia, by modulating gene expression through chromatin remodeling. HDACis such as suberoylanilide hydroxamic acid (SAHA), trichostatin A, and MS-27-275 have been studied extensively for their ability to alter gene expression profiles, leading to the upregulation of tumor suppressor genes and the downregulation of genes involved in cell cycle and apoptosis (Glaser et al., 2003). SAHA, in particular, has demonstrated significant anticancer activity in clinical trials and has been shown to induce changes in the acetylation and methylation of core histones, thereby increasing the accessibility of the p21 (WAF1) promoter to transcriptional machinery (Gui et al., 2004). Additionally, HDACis have been found to decrease the stability of DNMT3B mRNA, leading to reduced de novo DNA methylation activity, which further underscores their potential in epigenetic therapy (Xiong et al., 2005). 8.2 DNA methyltransferase inhibitors DNA methyltransferase inhibitors (DNMTis) are another class of epigenetic agents that have garnered attention for their ability to reverse aberrant DNA methylation patterns associated with various diseases. These inhibitors, such as 5-aza-2'-deoxycytidine (ADC), have been shown to reactivate silenced genes by demethylating DNA. The combination of DNMTis with HDACis has been particularly effective, as HDACis can enhance the demethylating effects of DNMTis, leading to a more pronounced reactivation of silenced genes (Xiong et al., 2005). This synergistic effect has been observed in various cancer models and holds potential for the treatment of sickle cell anemia by reactivating fetal hemoglobin (HbF) production, which can ameliorate the symptoms of the disease (Xu, and Yu, 2020). 8.3 Gene editing and epigenome editing technologies Recent advancements in gene editing and epigenome editing technologies, such as CRISPR/Cas9 and CRISPR/dCas9, have opened new avenues for the treatment of genetic disorders, including sickle cell anemia. These technologies allow for precise modifications of the genome and epigenome, enabling the correction of
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