Shreevatsa Bhargav, Nagaraj Abhigna, Dharmashekar Chandan, Jain Anisha, Harendra Bhavana, Siddalingegowda Siddesh V, Al-Mazroua Haneen A, Ahmad Sheikh F, Prasad Shashanka K, Srinivasa Chandrashekar, Shivamallu Chandan, Kollur Shiva Prasad
Department of Microbiology, JSS Academy of Higher Education and Research, Mysuru, India.
Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States.
Front Chem. 2025 Feb 5;13:1548269. doi: 10.3389/fchem.2025.1548269. eCollection 2025.
Multiple sclerosis (MS) is a chronic autoimmune illness characterized by demyelination, neurodegeneration, and inflammation in the central nervous system. The AXL gene, which codes for a receptor tyrosine kinase, has emerged as a promising therapeutic target due to its involvement in neuroinflammation and oligodendrocyte dysfunction. In the current study, we employed techniques to design Antisense Oligonucleotides (ASOs) that selectively target AXL gene transcripts to modulate AXL expression and mitigate MS pathology. Three ASOs, A1, A2, and A3, were designed to specifically target the 5' untranslated region (5'UTR) and coding region of the AXL gene transcripts. The ASOs were optimized with a focus on stability, binding affinity, and specificity towards AXL mRNA while minimizing off-target effects. To investigate ASO-mRNA interactions and gauge their ability to alter AXL expression, Molecular Docking was performed. Our analyses showed that A1, A2, and A3 had substantial interactions with AXL mRNA, with binding affinities of -9.5 kcal/mol, -10.8 kcal/mol, and -10.6 kcal/mol, respectively. The targeting of AXL gene transcripts through ASOs shows promise in reducing MS symptoms. Precision ASO-based therapies could effectively manage MS by targeting the essential pathways involved in the disease. ASOs provide a highly targeted approach for treating MS and offer a precise therapeutic strategy for this debilitating condition. The study lays the groundwork for future and studies to confirm the therapeutic potential of these ASOs for the treatment of MS.
多发性硬化症（MS）是一种慢性自身免疫性疾病，其特征是中枢神经系统出现脱髓鞘、神经退行性变和炎症。编码受体酪氨酸激酶的AXL基因，由于其参与神经炎症和少突胶质细胞功能障碍，已成为一个有前景的治疗靶点。在本研究中，我们采用技术设计反义寡核苷酸（ASO），选择性靶向AXL基因转录本以调节AXL表达并减轻MS病理。设计了三种ASO，A1、A2和A3，以特异性靶向AXL基因转录本的5'非翻译区（5'UTR）和编码区。对ASO进行了优化，重点关注其稳定性、结合亲和力以及对AXL mRNA的特异性，同时尽量减少脱靶效应。为了研究ASO与mRNA的相互作用并评估它们改变AXL表达的能力，进行了分子对接。我们的分析表明，A1、A2和A3与AXL mRNA有大量相互作用，结合亲和力分别为-9.5 kcal/mol、-10.8 kcal/mol和-10.6 kcal/mol。通过ASO靶向AXL基因转录本在减轻MS症状方面显示出前景。基于精准ASO的疗法可以通过靶向疾病相关的关键途径有效控制MS。ASO为治疗MS提供了一种高度靶向的方法，并为这种使人衰弱的疾病提供了精确的治疗策略。该研究为未来进一步研究证实这些ASO治疗MS的潜力奠定了基础。
