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iPSC-derived Disease Model Highlights Potential Treatment for Autoinflammatory Disorders

Review of “Pluripotent Stem Cell-based Screening Identifies CUDC-907 as an Effective Compound for Restoring the in Vitro Phenotype of Nakajo-Nishimura Syndrome” from STEM CELLS Translational Medicine by Stuart P. Atkinson

A homozygous mutation in the proteasome subunit beta 8 (PSMB8) gene (which encodes the β5i immunoproteasome subunit [1]) causes Nakajo‐Nishimura syndrome, an autoinflammatory disorder that advances from rashes and fevers during infancy to lipomuscular atrophy and joint contractures in later life [2]. In an attempt to study the pathophysiology of Nakajo‐Nishimura syndrome in detail, researchers led by Megumu K. Saito (Kyoto University, Kyoto, Japan) established induced pluripotent stem cells (iPSCs) carrying the disease‐associated PSMB8 mutation [3] and created an in vitro model via the differentiation of these iPSCs into myeloid cell lines (NNS-MLs) [4-6]. These cells reproduce inflammatory phenotypes, including the overproduction of monocyte chemoattractant protein‐1 (MCP‐1) and interferon gamma‐induced protein‐10 (IP‐10) [3, 7].

In a more recent STEM CELLS Translational Medicine article [8], Kase et al. established a high‐throughput compound screening system using the iPSC-derived NNS-MLs in the hope of encountering therapeutically-relevant candidate molecules. Excitingly, the authors now demonstrate that a histone deacetylase inhibitor may represent a potent means to ameliorate the overproduction of inflammatory chemokines in this autoinflammatory disorder.

The authors screened a compound library consisting of nearly 6000 compounds, including approved drugs, kinase inhibitors, and bioactive chemicals in their iPSC-derived NNS-MLs to search for a compound with the potential to inhibit MCP-1 and IP-10 overproduction. The authors highlighted the ease-of-use of iPSC-derived NNS-MLs, which can easily be propagated, passed through freeze/thaw cycles, and differentiated into functional macrophages or dendritic cells. As the lead candidate from this screen, histone deacetylase and PI3K‐Akt dual inhibitor CUDC‐907 [9] effectively reduced the overproduction of inflammatory chemokines without inducing cell death by inhibiting their translation. Even more encouragingly, the authors recapitulated some of these findings in primary patient fibroblasts.

Overall, the authors highlight their iPSC-derived NNS-ML model as an exciting new platform for the identification of novel therapeutic compounds for congenital immunological disorders. Their upcoming research aims include the delineation of the molecular mechanisms involved in the CUDC‐907-mediated downregulation of MCP-1 and IP-10 production.

For more on how iPSC-derived disease models can highlight novel treatment options for autoinflammatory disorders such as Nakajo‐Nishimura syndrome, stay tuned to the Stem Cells Portal!


  1. Murata S, Takahama Y, Kasahara M, et al., The immunoproteasome and thymoproteasome: functions, evolution and human disease. Nature Immunology 2018;19:923-931.
  2. Arima K, Kinoshita A, Mishima H, et al., Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proceedings of the National Academy of Sciences 2011;108:14914.
  3. Honda-Ozaki F, Terashima M, Niwa A, et al., Pluripotent Stem Cell Model of Nakajo-Nishimura Syndrome Untangles Proinflammatory Pathways Mediated by Oxidative Stress. Stem Cell Reports 2018;10:1835-1850.
  4. Shiba T, Tanaka T, Ida H, et al., Functional evaluation of the pathological significance of MEFV variants using induced pluripotent stem cell-derived macrophages. Journal of Allergy and Clinical Immunology 2019;144:1438-1441.e12.
  5. Takada S, Kambe N, Kawasaki Y, et al., Pluripotent stem cell models of Blau syndrome reveal an IFN-γ–dependent inflammatory response in macrophages. Journal of Allergy and Clinical Immunology 2018;141:339-349.e11.
  6. Kawasaki Y, Oda H, Ito J, et al., Identification of a High-Frequency Somatic NLRC4 Mutation as a Cause of Autoinflammation by Pluripotent Cell–Based Phenotype Dissection. Arthritis & Rheumatology 2017;69:447-459.
  7. Haruta M, Tomita Y, Imamura Y, et al., Generation of a large number of functional dendritic cells from human monocytes expanded by forced expression of cMYC plus BMI1. Human Immunology 2013;74:1400-1408.
  8. Kase N, Terashima M, Ohta A, et al., Pluripotent stem cell-based screening identifies CUDC-907 as an effective compound for restoring the in vitro phenotype of Nakajo-Nishimura syndrome. STEM CELLS Translational Medicine 2021;10:455-464.
  9. Qian C, Lai C-J, Bao R, et al., Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling. Clinical Cancer Research 2012;18:4104.