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Pluripotent stem cell-based screening identifies CUDC-907 as an effective compound for restoring the in vitro phenotype of Nakajo-Nishimura syndrome

2020; Wiley; Volume: 10; Issue: 3 Linguagem: Inglês

10.1002/sctm.20-0198

2157-6580

Naoya Kase, Madoka Terashima, Akira Ohta, Akira Niwa, Fumiko Honda‐Ozaki, Yuri Kawasaki, Tatsutoshi Nakahata, Nobuo Kanazawa, Megumu K. Saito,

Immunotherapy and Immune Responses

Abstract 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.