Cao Yangyue, Zhang Jingxiao, Wang Jiawei
Department of Neurology, Beijing Tongren Hospital, Capital Medical University, No. 1 Dongjiaominxiang Road, Beijing, 100730, China.
Mol Neurobiol. 2025 May;62(5):5518-5530. doi: 10.1007/s12035-024-04612-8. Epub 2024 Nov 20.
Neuromyelitis optica spectrum disorder (NMOSD) is a severe central nervous system disease primarily characterized by optic neuritis and myelitis, which can result in vision loss and limb paralysis. Current treatment options are limited in their ability to prevent relapses and mitigate disease progression, underscoring the urgent need for new drug targets to develop more effective therapies. The objective of this study is to identify potential drug targets associated with a reduced risk of NMOSD attacks or relapses through Mendelian randomization (MR) analysis, thereby addressing the limitations of existing treatment methods and providing better clinical options for patients. To identify therapeutic targets for NMOSD, a MR analysis was conducted. The cis-expression quantitative trait loci (cis-eQTL, exposure) data were sourced from the eQTLGen consortium, which included a sample size of 31,684. NMOSD (outcome) summary data were obtained from two of the largest independent cohorts: one cohort consisted of 86 NMOSD cases and 460 controls derived from whole-genome sequencing data, while the other cohort included 129 NMOSD patients and 784 controls. We performed a two-sample MR analysis to evaluate the association between single nucleotide polymorphisms (SNPs) and copy number variations with NMOSD. The MR analysis utilized the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses were conducted to assess the presence of horizontal pleiotropy and heterogeneity. Colocalization analysis was employed to test whether NMOSD risk and gene expression are driven by common SNPs. Additionally, a phenome-wide association study (PheWAS) was performed to detect disease outcomes associated with NEU1. Supplementary analyses included single-nucleus RNA sequencing (snRNA-seq) data analysis, protein-protein interaction (PPI) networks, and drug feasibility assessments to prioritize potential therapeutic targets. Two drug targets, COL4A1 and NEU1, demonstrated significant MR results in two independent datasets. Notably, NEU1 showed substantial evidence of colocalization with NMOSD. Additionally, apart from the association between NEU1 and NMOSD, no other associations were observed between gene-proxied NEU1 inhibition and the increased risk of other NMOSD-related diseases. This study supports the potential of targeting NEU1 for drug inhibition to reduce the risk of NMOSD. Further preclinical research and drug development are warranted to validate the efficacy and safety of NEU1 as a therapeutic target and to explore its potential in NMOSD treatment.
视神经脊髓炎谱系障碍（NMOSD）是一种严重的中枢神经系统疾病，主要特征为视神经炎和脊髓炎，可导致视力丧失和肢体瘫痪。目前的治疗方案在预防复发和减轻疾病进展方面能力有限，这凸显了开发更有效疗法的新药物靶点的迫切需求。本研究的目的是通过孟德尔随机化（MR）分析确定与NMOSD发作或复发风险降低相关的潜在药物靶点，从而解决现有治疗方法的局限性，并为患者提供更好的临床选择。为了确定NMOSD的治疗靶点，进行了一项MR分析。顺式表达定量性状位点（cis-eQTL，暴露）数据来自eQTLGen联盟，其样本量为31684。NMOSD（结局）汇总数据来自两个最大的独立队列：一个队列由86例NMOSD病例和460例来自全基因组测序数据的对照组成，而另一个队列包括129例NMOSD患者和784例对照。我们进行了两样本MR分析，以评估单核苷酸多态性（SNP）和拷贝数变异与NMOSD之间的关联。MR分析采用逆方差加权（IVW）方法，并辅以MR-Egger、加权中位数、简单模式和加权模式方法。进行敏感性分析以评估水平多效性和异质性的存在。采用共定位分析来检验NMOSD风险和基因表达是否由常见SNP驱动。此外，还进行了全表型关联研究（PheWAS）以检测与NEU1相关的疾病结局。补充分析包括单核RNA测序（snRNA-seq）数据分析、蛋白质-蛋白质相互作用（PPI）网络和药物可行性评估，以对潜在治疗靶点进行优先级排序。两个药物靶点COL4A1和NEU1在两个独立数据集中显示出显著的MR结果。值得注意的是，NEU1显示出与NMOSD共定位的大量证据。此外，除了NEU1与NMOSD之间的关联外，未观察到基因代理的NEU1抑制与其他NMOSD相关疾病风险增加之间的其他关联。本研究支持靶向NEU1进行药物抑制以降低NMOSD风险的潜力。有必要进行进一步的临床前研究和药物开发，以验证NEU1作为治疗靶点的有效性和安全性，并探索其在NMOSD治疗中的潜力。
