CuATSM effectively ameliorates ALS patient astrocyte-mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis.
CuATSM effectively ameliorates ALS patient astrocyte-mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis.
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DOI：
10.1002/glia.24278
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发表时间：
2023-02
期刊：
影响因子：
6.2
通讯作者：
Meyer, Kathrin
中科院分区：
文献类型：
--
作者：
Dennys, Cassandra N.;Roussel, Florence;Rodrigo, Rochelle;Zhang, Xiaojin;Delgado, Andrea Sierra;Hartlaub, Annalisa;Saelim-Ector, Asya;Ray, Will;Heintzman, Sarah;Fox, Ashley;Kolb, Stephen J.;Beckman, Joseph;Franco, Maria Clara;Meyer, Kathrin
患者的多样性和未知的病因是肌萎缩侧索硬化症（ALS）药物开发和临床试验设计的主要挑战。转基因动物模型不能充分反映ALS的异质性。将患者成纤维细胞直接重编程为神经元祖细胞并随后分化为患者星形胶质细胞允许快速产生疾病相关细胞类型。因此，该方法可以促进在不同遗传背景中的化合物测试，从而产生用于治疗评价的更具代表性的群体。在这里，我们使用已建立的运动神经元和重编程患者皮肤源性星形胶质细胞（iAs）的共培养试验来评估（SP-4 - 2）-[[2，2 '-（1，2-二甲基-1，2-亚乙基）双[N-甲基肼硫代氨基甲酸-κN 2，κS]]（2-）]-铜（CuATSM）的作用，该药物目前正在澳大利亚进行ALS的临床试验。用CuATSM预处理iAs对与健康运动神经元共培养后的神经元存活具有不同的影响。使用该测定，我们鉴定了散发性和家族性ALS（突变体SOD 1和C9 ORF 72）的应答和非应答细胞系。重要的是，线粒体呼吸升高是所有CuATSM应答者的共同特征，这是一种在非应答者中未观察到的代谢表型。用CuATSM预处理iAs使线粒体活性恢复至与健康对照相当的水平。因此，该代谢参数可能允许选择最适合CuATSM治疗的患者亚群。此外，CuATSM可能对线粒体疾病具有额外的治疗价值。加强对患者特异性细胞和分子谱的理解有助于改善未来的临床试验设计。临床阶段药物CuATSM使ALS星形胶质细胞的异常代谢表型正常化，并恢复对神经元的支持。患者样本可以根据该表型进行分层，表明模型系统可能支持临床试验结果解释或设计。
Patient diversity and unknown disease cause are major challenges for drug development and clinical trial design for amyotrophic lateral sclerosis (ALS). Transgenic animal models do not adequately reflect the heterogeneity of ALS. Direct reprogramming of patient fibroblasts to neuronal progenitor cells and subsequent differentiation into patient astrocytes allows rapid generation of disease relevant cell types. Thus, this methodology can facilitate compound testing in a diverse genetic background resulting in a more representative population for therapeutic evaluation. Here, we used established co‐culture assays with motor neurons and reprogrammed patient skin‐derived astrocytes (iAs) to evaluate the effects of (SP‐4‐2)‐[[2,2’‐(1,2‐dimethyl‐1,2‐ethanediylidene)bis[N‐methylhydrazinecarbothioamidato‐κN 2 ,κS]](2‐)]‐copper (CuATSM), currently in clinical trial for ALS in Australia. Pretreatment of iAs with CuATSM had a differential effect on neuronal survival following co‐culture with healthy motor neurons. Using this assay, we identified responding and non‐responding cell lines for both sporadic and familial ALS (mutant SOD1 and C9ORF72). Importantly, elevated mitochondrial respiration was the common denominator in all CuATSM‐responders, a metabolic phenotype not observed in non‐responders. Pre‐treatment of iAs with CuATSM restored mitochondrial activity to levels comparable to healthy controls. Hence, this metabolic parameter might allow selection of patient subpopulations best suited for CuATSM treatment. Moreover, CuATSM might have additional therapeutic value for mitochondrial disorders. Enhanced understanding of patient‐specific cellular and molecular profiles could help improve clinical trial design in the future. The clinical stage drug CuATSM normalizes aberrant metabolic phenotypes of ALS astrocytes and restores support towards neurons. Patient samples could be stratified based on this phenotype, indicating that the model system might support clinical trial result interpretation or design.
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DOI：
10.1073/pnas.1116227108
发表时间：
2012-01-03
影响因子：
11.1
作者：
Donnelly, Paul S.;Liddell, Jeffrey R.;Crouch, Peter J.
通讯作者：
Crouch, Peter J.
影响因子：
3.3
作者：
AGNOLI, A;BALDASSARRE, M;ROCCO, A
通讯作者：
ROCCO, A
影响因子：
11
作者：
FACTOR, SA;SANCHEZRAMOS, JR;INGENITO, AM
通讯作者：
INGENITO, AM
影响因子：
25
作者：
Bosco, Daryl A.;Morfini, Gerardo;Karabacak, N. Murat;Song, Yuyu;Gros-Louis, Francois;Pasinelli, Piera;Goolsby, Holly;Fontaine, Benjamin A.;Lemay, Nathan;McKenna-Yasek, Diane;Frosch, Matthew P.;Agar, Jeffrey N.;Julien, Jean-Pierre;Brady, Scott T.;Brown, Robert H., Jr.
通讯作者：
Brown, Robert H., Jr.
影响因子：
11.2
作者：
Beal, MF;Ferrante, RJ;Brown, RH
通讯作者：
Brown, RH