Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
Department of Fundamental Cell Technology, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
Stem Cells Transl Med. 2021 Mar;10(3):455-464. doi: 10.1002/sctm.20-0198. Epub 2020 Oct 14.
Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in the PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)-derived NNS disease model that reproduces several inflammatory phenotypes, including the overproduction of monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein-10 (IP-10). Here we performed high-throughput compound screening (HTS) using this PSC-derived NNS model to find potential therapeutic candidates and identified CUDC-907 as an effective inhibitor of the release of MCP-1 and IP-10. Short-term treatment of CUDC-907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post-transcriptional. These findings suggest that HTS with PSC-derived disease models is useful for finding drug candidates for autoinflammatory diseases.
Nakajo-Nishimura 综合征（NNS）是一种由 PSMB8 基因纯合突变引起的自身炎症性疾病。全身皮质类固醇的给药部分有效，但持续治疗会引起严重的副作用。我们之前建立了一种多能干细胞（PSC）衍生的 NNS 疾病模型，该模型可再现几种炎症表型，包括单核细胞趋化蛋白-1（MCP-1）和干扰素γ诱导蛋白-10（IP-10）的过度产生。在这里，我们使用这种 PSC 衍生的 NNS 模型进行了高通量化合物筛选（HTS），以寻找潜在的治疗候选物，并确定 CUDC-907 是 MCP-1 和 IP-10 释放的有效抑制剂。CUDC-907 的短期治疗在治疗浓度内不会诱导细胞死亡，对原代患者细胞也有效。进一步的分析表明，抑制作用是转录后性的。这些发现表明，使用 PSC 衍生的疾病模型进行 HTS 对于寻找自身炎症性疾病的药物候选物是有用的。
