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

Abstract

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. 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. K E Y W O R D S chemokines, hereditary autoinflammatory diseases, high-throughput screening assays, histone deacetylase inhibitors, LMP7 protein, pluripotent stem cells 1 | INTRODUCTION Proteasome-associated autoinflammatory syndromes (PRAAS) are a recently defined group of autoinflammatory disorders caused by the mutations of proteasome subunits or their assembly factors. 1 PRAAS include diseases such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), 2 POMP-related auto-inflammation and immune dysregulation disease (PRAID), 3 and

High-Yield Human Induced Pluripotent Stem Cell-Derived Monocytes and Macrophages Are Functionally Comparable With Primary Cells

“…Different from recently reported protocols of monocyte differentiation (Gutbier et al, 2020), we used the 2D culture setting, starting from the single clones instead of the 3D culture of embryonic bodies. The hiPSCs were firstly induced into mesoderm and further differentiated into HE and HPCs with high efficiency (Matsubara et al, 2019;Ohta et al, 2019;Kase et al, 2020), and at this stage, the cells can be expanded for an additional 7 days and conveniently cryopreserved depending on the scaling and timing demands of the following experimental procedures and scientific objectives. The HPCs were then further directed to MPs and monocytes in 10 days.…”

“…The differentiation protocol is fully optimized and largely improved in aspects of the timing of steps and additional cytokines, chemokines, or chemicals, compared with the previously published protocol (Yanagimachi et al, 2013;Matsubara et al, 2019;Ohta et al, 2019;Kase et al, 2020). The differentiation procedure (Figure 1A) was carried out in serum-free conditions.…”

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“…Furthermore, the team established a Nakajo‐Nishimura syndrome disease model by generating myeloid cell lines from iPSC‐derived monocytes that reproduced disease‐specific inflammatory phenotypes 20 . In a recent STEM CELLS Translational Medicine article, 10 Kase et al employed a high‐throughput compound screening system employing their iPSC‐derived myeloid cells (NNS‐MLs) to identify an HDAC inhibitor as a potentially exciting means to constrain the overproduction of inflammatory chemokines (monocyte chemoattractant protein‐1 [MCP‐1] and interferon gamma‐induced protein‐10 [IP‐10]) associated with this autoinflammatory disorder. The authors screened a compound library of nearly 6000 compounds, including approved drugs, kinase inhibitors, and bioactive chemicals, in the search for a compound that could reduce MCP‐1 and IP‐10 overproduction.…”

“…9 In a Related Article published recently in STEM CELLS Translational Medicine, Kase et al employed an iPSC-based screening to identify an HDAC inhibitor as a candidate treatment to reduce the overproduction of inflammatory chemokines associated with an autoinflammatory disease. 10…”

“…In the second of our Featured Articles published this month in STEM CELLS , Liu et al describe how an HDAC‐associated complex regulates the osteogenic differentation and therapeutic potential of mesenchymal stem cells (MSCs) in a study that sheds new light on bone regeneration strategies 9 . In a Related Article published recently in STEM CELLS Translational Medicine , Kase et al employed an iPSC‐based screening to identify an HDAC inhibitor as a candidate treatment to reduce the overproduction of inflammatory chemokines associated with an autoinflammatory disease 10 …”