Effects of PB-TURSO on the transcriptional and metabolic landscape of sporadic ALS fibroblasts.
Effects of PB-TURSO on the transcriptional and metabolic landscape of sporadic ALS fibroblasts.
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DOI：
10.1002/acn3.51648
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发表时间：
2022-10
影响因子：
5.3
通讯作者：
Kawamata, Hibiki
中科院分区：
文献类型：
--
作者：
Fels, Jasmine A.;Dash, Jalia;Leslie, Kent;Manfredi, Giovanni;Kawamata, Hibiki
肌萎缩性侧索硬化症是一种由运动神经元退化引起的快速进展的致命疾病，其治疗需求尚未得到满足。AMX0035是一种苯基丁酸钠（PB）和牛磺酸钠（TUDCA， TURSO）的组合药物，在早期ALS临床试验中显示出良好的效果，但其作用机制仍有待阐明。因此，我们的目标是获得AMX0035在ALS患者来源细胞中的分子效应的公正景观。我们研究了散发性ALS患者和健康对照组（n = 12/组）接受PB、TUDCA或PB - TUDCA联合（Combo）治疗的原发性皮肤成纤维细胞的转录组学和代谢组学特征。数据通过多种方法进行评估，包括差异基因表达和代谢物丰度、基因本体和代谢途径分析、加权基因共表达相关分析（WGCNA）和联合多组学综合分析。与单独使用PB或TUDCA相比，Combo改变了更多的基因和代谢物。大多数变化是Combo所特有的，影响涉及核胞质转运、未折叠蛋白反应、线粒体功能、RNA代谢和先天免疫的基因的表达。WGCNA显示，ALS基因表达模块与临床参数之间存在显著相关性，而联合治疗消除了这一相关性。这项研究首次探索了Combo在ALS患者来源细胞中的分子效应。结果表明，与单独的化合物相比，Combo具有更大、更明显的影响，并为药物靶点和作用机制提供了线索，这可能是该研究药物组合益处的基础。
ALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there is a great unmet therapeutic need. AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, TURSO), has shown promising results in early ALS clinical trials, but its mechanisms of action remain to be elucidated. Therefore, our goal was to obtain an unbiased landscape of the molecular effects of AMX0035 in ALS patient‐derived cells. We investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls (n = 12/group) treated with PB, TUDCA, or PB–TUDCA combination (Combo). Data were evaluated with multiple approaches including differential gene expression and metabolite abundance, Gene Ontology and metabolic pathway analysis, weighted gene co‐expression correlation analysis (WGCNA), and combined multiomics integrated analysis. Combo changed many more genes and metabolites than either PB or TUDCA individually. Most changes were unique to Combo and affected the expression of genes involved in nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. WGCNA showed significant correlations between ALS gene expression modules and clinical parameters that were abolished by Combo treatment. This study is the first to explore the molecular effects of Combo in ALS patient‐derived cells. It shows that Combo has a greater and distinct impact compared with the individual compounds and provides clues to drug targets and mechanisms of action, which may underlie the benefits of this investigational drug combination.
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影响因子：
16.2
作者：
Kim HJ;Taylor JP
通讯作者：
Taylor JP
影响因子：
17.1
作者：
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--
影响因子：
17.1
作者：
通讯作者：
--
影响因子：
5.6
作者：
Grant SM;DeMorrow S
通讯作者：
DeMorrow S
影响因子：
3
作者：
Iannitti T;Palmieri B
通讯作者：
Palmieri B