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Induced Pluripotent Stem (iPS) Cell Research Unit for Drug Discovery Aiming a pipeline below for drug development against human diseases
Disease-specific iPS cell ~ Disease model cell ~ Discover effective natural product ~ Unveil mechanism ~ Drug development

Studying diseases using disease-specific iPS cells

iPS cells derived from patients (disease-specific iPS cells or patient-specific iPS cells) opened an innovative way for disease research . For example, isolating brain tissues from patients suffering from brain diseases is impossible. In this case, iPS cells can be generated with skin or blood cells of patients, and brain cells can be induced from these iPS cells; therefore, we can obtain a model of diseased cells and study them. In addition, biopsies of the heart, liver, kidney, and other organs are necessary in the clinic; however, these procedures are highly risky. The model cells obtain from iPS cells may possibly fulfil the necessity of these biopsies.

Images of colonies of human fibrocytes and human iPS cells

Searching for and identification of target cells (disease-causing and/or associated cells) through disease-specific iPS cells

In relation to many intractable diseases, target cells (disease-causing and/or associated cells) have not yet been identified. Putative target cells can be induced from disease-specific iPS cells, and their phenotypes can be compared with equivalent cells derived from iPS cells of healthy individuals. This kind of analysis will identify target cells and unveil causes and mechanisms of diseases.

Culture target cells (disease-causing and/or associated cells) through disease-specific iPS cells

Assay development for drug screening using model cells derived from disease-specific iPS cells

This unit aims to develop bioassays for drug screening using disease-model cells derived from disease-specific iPS cells, in which candidate chemicals will be tested for their efficacy to improve phenotypes of disease-model cells. In addition, this unit will develop methods to efficiently and abundantly produce disease-model cells and provide them for drug screening.

Innovative drug discovery research using disease-specific iPS cells

Current situation in this field

By applying the above-mentioned strategy, many candidate drugs have already been discovered out of known drugs or as quite novel drugs with several published reports.

  1. Honda Y, Li J, Hino A, Tsujimoto S, Lee JK. High-Throughput Drug Screening System Based on Human Induced Pluripotent Stem Cell-Derived Atrial Myocytes: A Novel Platform to Detect Cardiac Toxicity for Atrial Arrhythmias. Front Pharmacol. 2021 Aug 3; 12: 680618. doi: 10.3389/fphar.2021.680618. eCollection 2021. PMID: 34413773
  2. Imamura K, Sakurai Y, Enami T, Shibukawa R, Nishi Y, Ohta A, Shu T, Kawaguchi J, Okada S, Hoenen T, Yasuda J, Inoue H. iPSC screening for drug repurposing identifies anti-RNA virus agents modulating host cell susceptibility. FEBS Open Bio. 2021 May; 11(5): 1452-1464. doi: 10.1002/2211-5463.13153. Epub 2021 Apr 6. PMID: 33822489
  3. Kase N, Terashima M, Ohta A, Niwa A, Honda-Ozaki F, Kawasaki Y, Nakahata T, Kanazawa N, Saito MK. Pluripotent stem cell-based screening identifies CUDC-907 as an effective compound for restoring the in vitro phenotype of Nakajo-Nishimura syndrome. Stem Cells Transl Med. 2021 Mar; 10(3): 455-464. doi: 10.1002/sctm.20-0198. Epub 2020 Oct 14. PMID: 33280267
  4. Yamaguchi A, Ishikawa KI, Inoshita T, Shiba-Fukushima K, Saiki S, Hatano T, Mori A, Oji Y, Okuzumi A, Li Y, Funayama M, Imai Y, Hattori N, Akamatsu W. Identifying Therapeutic Agents for Amelioration of Mitochondrial Clearance Disorder in Neurons of Familial Parkinson Disease. Stem Cell Reports. 2020 Jun 9; 14(6): 1060-1075. doi: 10.1016/j.stemcr.2020.04.011. Epub 2020 May 28. PMID: 32470327
  5. Seki R, Ohta A, Niwa A, Sugimine Y, Naito H, Nakahata T, Saito MK. Induced pluripotent stem cell-derived monocytic cell lines from a NOMID patient serve as a screening platform for modulating NLRP3 inflammasome activity. PLoS One. 2020 Aug 18; 15(8): e0237030. doi: 10.1371/journal.pone.0237030. eCollection 2020. PMID: 32810141
  6. Kokubu Y, Nagino T, Sasa K, Oikawa T, Miyake K, Kume A, Fukuda M, Fuse H, Tozawa R, Sakurai H. Phenotypic Drug Screening for Dysferlinopathy Using Patient-Derived Induced Pluripotent Stem Cells. Stem Cells Transl Med. 2019 Oct; 8(10): 1017-1029. doi: 10.1002/sctm.18-0280. Epub 2019 Jun 28. PMID: 31250983
  7. Takada H, Kaieda A, Tawada M, Nagino T, Sasa K, Oikawa T, Oki A, Sameshima T, Miyamoto K, Miyamoto M, Kokubu Y, Tozawa R, Sakurai H, Saito B. Identification of 2,6-Disubstituted 3H-Imidazo[4,5-b]pyridines as Therapeutic Agents for Dysferlinopathies through Phenotypic Screening on Patient-Derived Induced Pluripotent Stem Cells. J Med Chem. 2019 Oct 24; 62(20): 9175-9187. doi: 10.1021/acs.jmedchem.9b01100. Epub 2019 Oct 7. PMID: 31550153

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