基于可变剪接的神经退行性疾病治疗：双数据库文献计量学与自然语言处理驱动分析（2000-2025）

摘要(中文译文)

神经退行性疾病（NDDs）由复杂的分子调控异常驱动，其中异常可变剪接（AS）已成为关键的致病机制。尽管包括反义寡核苷酸（ASOs）和小分子在内的剪接靶向治疗药物发展迅速，但全面描绘这一转化研究格局的大数据综合研究仍然匮乏。本研究采用文献计量学与自然语言处理（NLP）相结合的综合方法，系统分析AS为基础的治疗策略应用于NDDs的全球研究趋势、概念框架及临床演进。采用双数据库检索策略，利用Web of Science核心合集（WoSCC）和PubMed进行检索。分析聚焦于2000年1月1日至2025年12月31日期间发表的文献。从WoSCC提取620条记录作为主要数据集，用于全面的文献计量学图谱构建和潜在狄利克雷分配（LDA）主题建模。平行分析纳入PubMed中10项靶向临床试验和随机对照试验（RCTs），采用CLARA聚类以刻画高证据等级研究。文献计量学分析涵盖网络拓扑结构、引文突现和关键词演化，使用VOSviewer、CiteSpace、SCImago和R进行可视化。2000年至2025年发文量呈持续线性增长。美国和西欧成为主要合作枢纽，而中国表现出高产出但国际整合有限。LDA主题建模识别出三个核心概念轴：分子机制、疾病特异性病理模型（如ALS、阿尔茨海默病和SMA）以及转化方法学框架。关键词轨迹描绘了从基础探索到模型研究的转变，最终聚焦于临床“药物发现”和“RNA”治疗。临床试验的CLARA聚类显示，剪接修饰干预措施显著集中于儿童脊髓性肌萎缩症（SMA），揭示了支持性护理与分子干预并行的双轨模式。这项多数据库文献计量学与NLP驱动的研究勾勒了AS为基础的治疗策略应用于NDDs的结构性格局。研究明确了从描述性分子生物学向临床可操作的剪接干预的范式转变。这些见解凸显了将靶向RNA平台从SMA拓展至成人神经退行性疾病人群的必要性，为未来转化研究提供了战略性路线图。

Abstract

Neurodegenerative diseases (NDDs) are driven by complex molecular dysregulation, among which aberrant alternative splicing (AS) has emerged as a critical pathogenic mechanism. Despite the rapid development of splicing-targeted therapeutics, including antisense oligonucleotides (ASOs) and small molecules, comprehensive big-data syntheses mapping this translational landscape remain scarce. This study systematically analyzes the global research trends, conceptual frameworks, and clinical evolution of AS-based therapeutics for NDDs using an integrated bibliometric and natural language processing (NLP) approach. A dual-database retrieval strategy utilized the Web of Science Core Collection (WoSCC) and PubMed. The analysis targeted literature published between January 1, 2000, and December 31, 2025. A primary dataset of 620 records was extracted from WoSCC for comprehensive bibliometric mapping and Latent Dirichlet Allocation (LDA) topic modeling. A parallel analysis incorporated 10 targeted clinical trials and randomized controlled trials (RCTs) from PubMed using CLARA clustering to characterize high-evidence research. Bibliometric analyses, encompassing network topologies, citation bursts, and keyword evolution, were visualized using VOSviewer, CiteSpace, SCImago, and R. Publication output exhibited sustained linear growth from 2000 to 2025. The United States and Western Europe emerged as the dominant collaborative hubs, while China exhibited high productivity but limited international integration. LDA topic modeling identified three core conceptual axes: molecular mechanisms, disease-specific pathological models (e.g., ALS, Alzheimer's, and SMA), and translational methodological frameworks. Keyword trajectories delineated a transition from fundamental exploration to models, culminating in clinical "drug discovery" and "RNA" therapeutics. CLARA clustering of clinical trials demonstrated a stark concentration of splicing-modifying interventions in pediatric spinal muscular atrophy (SMA), revealing a dual-track paradigm of supportive care and molecular interventions. This multi-database bibliometric and NLP-driven study delineates the structural landscape of AS-based therapeutics for NDDs. It identifies a definitive paradigm shift from descriptive molecular biology to clinically actionable splicing interventions. These insights highlight the necessity to expand targeted RNA platforms beyond SMA into adult neurodegenerative populations, providing a strategic roadmap for future translational research.

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