| Autor: |
Yuri Kawasaki, Akira Ohta, Naoya Kase, Tatsutoshi Nakahata, Akira Niwa, Fumiko Honda-Ozaki, Megumu K. Saito, Madoka Terashima, Nabuo Kanazawa |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.06.01.113894 |
| Popis: |
Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in 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. 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.Significance statementIn this study, we identified a histone deacetylase inhibitor CUDC-907 as a potential effective compound for ameliorating overproduction of inflammatory chemokines in an autoinflammatory disease named Nakajo-Nishimura syndrome. We performed high-throughput screening using pluripotent stem cell-derived monocytic cell lines. Our data prove the validity of screening system as a versatile platform for seeking candidate compounds for the treatment of congenital immunological disorders associated with monocytic lineage cells. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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