Galectin3: a novel biomarker of glycogen storage disease type III

Glycogen storage disease type III (GSDIII) is a rare genetic disease caused by mutations in the AGL gene, resulting in glycogen debranching enzyme (GDE) deficiency. There is currently no cure. Among various symptoms, skeletal muscle impairment represents a key target for the development of therapies. Identifying reliable biomarkers is crucial for evaluating new therapies, yet muscle-specific biomarkers for GSDIII are lacking. In this study, we generated GSDIII skeletal muscle cells derived from human-induced pluripotent stem cells that recapitulate the glycogen accumulation phenotype. A comparative gene expression analysis was carried out using RNA sequencing to identify novel biomarkers. Our results reports a significant overexpression of galectin-3 in both human and mouse models and patient biopsies, and a significant decrease in mice treated by an AAV gene therapy. Together, our results propose galectin-3 as a biomarker to assess therapeutic efficacy and GSDIII pathological monitoring in the muscle. Overall design: we performed a bulk RNA sequencing of the 3 CTRLs and the 4 GSDIIIPatients generated skMt. (Quantseq)

Ⅲ型糖原贮积症（Glycogen storage disease type III, GSDIII）是一类罕见遗传病，由AGL基因突变引发，可导致糖原脱支酶（glycogen debranching enzyme, GDE）缺乏，目前尚无治愈方案。在诸多临床症状中，骨骼肌损伤是疗法开发的核心靶点。鉴定可靠的生物标志物对评估新型治疗手段至关重要，但目前仍缺乏针对Ⅲ型糖原贮积症的肌肉特异性生物标志物。本研究利用人诱导多能干细胞（human-induced pluripotent stem cells）构建了可重现糖原累积表型的Ⅲ型糖原贮积症骨骼肌细胞模型。通过RNA测序（RNA sequencing）开展比较基因表达分析，以筛选新型候选生物标志物。研究结果显示，半乳糖凝集素-3（galectin-3）在人类、小鼠模型及患者活检样本中均呈现显著高表达；而经腺相关病毒（adeno-associated virus, AAV）基因疗法治疗的小鼠体内，半乳糖凝集素-3的表达水平显著下调。综上，本研究提出半乳糖凝集素-3可作为评估肌肉组织中Ⅲ型糖原贮积症治疗效果及病理监测的生物标志物。整体实验设计：本研究对3例对照样本及4例Ⅲ型糖原贮积症患者来源的骨骼肌细胞进行了批量RNA测序（bulk RNA sequencing），测序采用Quantseq技术。