Takeda Pharmaceutical Company Limited, Rare Disease Drug Discovery Unit, Cambridge, MA, USA.
Takeda Pharmaceutical Company Limited, Preclinical and Translational Sciences, Cambridge, MA, USA.
Ann Med. 2024 Dec;56(1):2402503. doi: 10.1080/07853890.2024.2402503. Epub 2024 Oct 24.
Acid α-glucosidase (GAA) is a lysosomal enzyme that hydrolyzes glycogen to glucose. Deficiency of GAA causes Pompe disease (PD), also known as glycogen storage disease type II. The resulting glycogen accumulation causes a spectrum of disease severity ranging from infantile-onset PD to adult-onset PD. Additional non-invasive biomarkers of disease severity are needed to monitor response to therapeutic interventions.
We measured protein and miRNA abundance in exosomes from serum and urine from the PD mouse model (B6;129-GaaTm1Rabn/J), wild-type mice, and PD mice treated with a candidate gene therapy.
There were significant differences in the abundance of 113 miRNA in serum exosomes from Pompe versus healthy mice. Levels of miR-206, miR-133, miR-1a, miR-486, and other important regulators of muscle development and maintenance were altered in the Pompe samples. The serum and urine exosome proteomes of healthy and Pompe mice also differed broadly. Several of the dysregulated proteins are encoded by genes with potential target sites for affected miRNA.
Exosomes derived from urine or serum are a potential source of biomarkers for Pompe Disease. Further study of the differences in the miRNA transcriptome and proteome content of exosomes may yield new insights into disease mechanisms.
酸性α-葡萄糖苷酶（GAA）是一种溶酶体酶，可将糖原水解为葡萄糖。GAA 的缺乏会导致庞贝病（PD），也称为糖原贮积症 II 型。由此产生的糖原积累导致疾病严重程度的一系列变化，从婴儿期起病的 PD 到成人起病的 PD。需要额外的非侵入性疾病严重程度生物标志物来监测治疗干预的反应。
我们测量了来自 PD 小鼠模型（B6;129-GaaTm1Rabn/J）、野生型小鼠以及用候选基因治疗治疗的 PD 小鼠的血清和尿液中外泌体中的蛋白质和 miRNA 丰度。
庞贝病与健康对照小鼠的血清外泌体中存在 113 种 miRNA 的丰度存在显著差异。在庞贝样本中，miR-206、miR-133、miR-1a、miR-486 和其他重要的肌肉发育和维持调节剂的水平发生了改变。健康和庞贝小鼠的血清和尿液外泌体蛋白质组也广泛不同。一些失调的蛋白质由受影响的 miRNA 的潜在靶基因编码。
来自尿液或血清的外泌体是庞贝病的潜在生物标志物来源。进一步研究外泌体中 miRNA 转录组和蛋白质组内容的差异可能会深入了解疾病机制。
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