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October 16, 2020

A drug candidate for an extremely rare autoimmune disease

The Megumu Saito laboratory combines iPS cell reprogramming and high-throughput drug screening system for Nakajo-Nishimura syndrome.

Nakajo-Nishimura syndrome is an autoimmune disease in which symptoms are seen early in infancy and include severe fevers, rashes and other ailments. The intensity of the inflammation can cause sudden cardiac failure. Doctors have tried to control the disease with steroids, but this only treats some of the symptoms and can cause its own set of health problems.

The disease is extremely rare, with only 30 cases known and all in Japan. In this regard, the laboratory of CiRA Associate Professor Megumu Saito is the only group in the world to have reprogrammed Nakajo-Nishimura syndrome patient cells into iPS cells in order to study the molecular factors that develop the disease. In the new study, they extend the work by complimenting it with a high throughput screening system to discover drugs that ameliorate the disease phenotype in cells.

"Nakajo-Nishimura syndrome is defined by a common mutation in the proteasome. Patients show high levels of the chemokines MCP-1 [monocyte chemoattractant protein-1] and IP-10 [interferon gamma-induced protein]," explains Saito, describing two of the key factors that cause the hyperinflammation.

The same two proteins are targets for treating other inflammatory diseases including rheumatoid arthritis.

The study used patient iPS cells made from the lab's previous work and differentiated them into myeloid cells for the drug screening. This led to the discovery of CUDC-907, which according to first author and Ph.D. student Naoya Kase, inhibits the enzyme histone deacetylase (HDAC).

"We found four compounds that could suppress the inflammation. One is already known, but the other three were all HDAC inhibitors. The anti-inflammatory effects of HDAC inhibitors are not yet understood and may become new therapeutic targets," he said, adding that of the three, CUDC-907 was the most effective.

The negative CUDC-907 effects on inflammation were confirmed in fibroblasts taken from the patient. In fact, the amount of MCP-1 and IP-10 in the patient myeloid and fibroblasts after treatment matched that found in cells from healthy donors.

Counterintuitively, however, while the protein levels of MCP-1 and IP-10 were reduced by CUDC-907 treatment, their gene expressions were actually increased.

"From our data, CUDC-907 has two different effects. One is elevation of mRNA expression. The other is suppression of protein production. Since HDAC inhibitors affect gene expressions via epigenetic changes, the two opposite effects may represent different mechanisms," explains Kase.

This contrast implies that the protein suppression is due to some yet unidentified post-transcriptional process. Saito notes that post-transcriptional irregularities in MCP-1 and IP-10 are seen in other diseases, making this a worthwhile strategy to investigate further in Nakajo-Nishimura syndrome.

"There are abnormal post-transcriptional processes of MCP-1 in asthma and IP-10 in diabetic retinopathy. We are researching if the same applies to Nakajo-Nishimura syndrome," he says.

Paper Details
  • Journal: STEM CELLS Translational Medicine
  • Title: Pluripotent stem cell‐based screening identifies CUDC‐907 as an effective compound for restoring the in vitro phenotype of Nakajo‐Nishimura syndrome
  • Authors: Naoya Kase1, Madoka Terashima1, Akira Ohta2, Akira Niwa1, Fumiko Honda-Ozaki1, Yuri Kawasaki1, Tatsutoshi Nakahata2, Nobuo Kanazawa3 and Megumu K. Saito1
  • Author Affiliations:
    1. Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
    2. Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
    3. Department of Dermatology, Wakayama Medical University, Wakayama, Japan
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