报告题目:

Human Neuromuscular Organoids as Translational Drug Discovery of CTGF-Targeted Aptamer to Alleviate Muscle Fibrosis and Neuromuscular Loss

报告人:

高充

所在单位:

广州中医药大学

报告人简介:

高充，博士，研究员，博士生导师，博士后合作导师。博士毕业于香港大学中医药学院，2026年2月通过“杏林青年高层次人才”引进计划入职广州中医药大学基础医学院。主要聚焦利用患者多能干细胞构建类器官模型，并应用于神经退行性疾病的中西医干预研究。现主持国家自然科学基金等项目4项，参编专著1部，获国家发明专利1项；以通讯作者或第一作者（含共同）在 Cell Reports、Coordination Chemistry Reviews、eBioMedicine等国际知名期刊发表SCI论文18篇，其中影响因子大于20的论文1篇。累计被引1200余次，H指数17，入选封面论文1篇。高充博士关于肌萎缩侧索硬化（Amyotrophic Lateral Sclerosis, ALS）患者iPSCs神经肌肉类器官模型构建及药物筛选的研究，受到 Signal Transduction and Targeted Therapy、Cell Stem Cell、Advanced Science、Pharmacological Research等高水平期刊的广泛引用，单篇最高被引56次。在此基础上，高充博士与西湖大学、广州国家实验室、浙江大学等团队紧密合作，在渐愈互助之家创始人、前京东集团副总裁蔡磊先生的支持下，共同推进国内ALS患者iPSCs生物样本库建设，已完成全国范围内179例ALS患者iPSCs重编程工作，并开发了可部署于临床中心的ALS患者自动分型及临床队列管理大模型工具（bioRxiv, doi: https://doi.org/10.64898/2026.02.01.703078）。高充博士现任香港大学深圳医院荣誉研究员、香港中文大学（深圳）福田研究院兼聘研究员；受邀担任 Metabolic Brain Disease杂志编委，以及 Nature Communications、Research、Phytomedicine、Genes&Diseases等期刊审稿专家。

报告摘要:

Skeletal muscle degeneration contributes substantially to functional decline in amyotrophic lateral sclerosis (ALS), yet peripheral tissue-remodeling mechanisms remain underexplored as therapeutic targets. Here, we integrated clinical skeletal muscle (SKM) biopsies, single-nucleus RNA sequencing, SOD1-G93A mice, and patient-derived neuromuscular organoids (NMOs), to define a CTGF-associated fibrotic remodeling program in ALS skeletal muscle. Single-nucleus profiling of ALS biopsies with or without fibrotic diagnosis identified a fibrogenic fibro-adipogenic progenitor (FAP) state enriched for extracellular matrix (ECM) organization and CTGF-associated remodeling. We tested our designed AP3, a chemically stabilized CTGF-targeting aptamer with high-affinity CTGF binding, and found favorable SKM pharmacokinetic properties, reduced skeletal muscle fibrosis, preserved neuromuscular junction integrity, improved motor performance, and enhanced the therapeutic effect of riluzole combination therapy in SOD1-G93A mice. Fibrotic ECM deposition, elevated CTGF protein, impaired neuromuscular junction integrity, and reduced contractile activity were recapitulated in ALS patient-derived NMOs across multiple genetic backgrounds. AP3 attenuated ECM deposition, restored neuromuscular junction architecture, and improved contractile function in ALS NMOs, in association with its regulatory function of COL12A mediated by TGFβ-2. Together, these findings identify a druggable CTGF-dependent fibrotic remodeling axis in ALS skeletal muscle and support anti-fibrotic aptamer therapy as a potential adjunct strategy to preserve neuromuscular function in ALS.