1: Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery.
Science of the Month - July 2023
Cell Stem Cell.
2023 Jun 1;30(6):766-780.e9. doi: 10.1016/j.stem.2023.04.017.
Morimoto S, Takahashi S, Ito D, Daté Y, Okada K, Kato C, Nakamura S, Ozawa F, Chyi CM, Nishiyama A, Suzuki N, Fujimori K, Kondo T, Takao M, Hirai M, Kabe Y, Suematsu M, Jinzaki M, Aoki M, Fujiki Y, Sato Y, Suzuki N, Nakahara J; Pooled Resource Open-Access ALS Clinical Trials Consortium; Okano H.
Drug discovery research using iPS cells is in its infancy, but successful examples are scarce, and the discrepancy between iPS cell models and actual clinical practice has been a particular problem. This paper reports the results of a Phase 1/2a investigator-initiated clinical trial of ropinirole hydrochloride (ROPI), which was identified as a drug candidate for amyotrophic lateral sclerosis (ALS) using iPS cell technology. ROPI was found to be safe to administer to ALS patients and showed an effect in suppressing the progression of ALS symptoms. Furthermore, iPS cells were established from all subjects and differentiated into motor neurons (MNs), the primary site of the lesion. The effects of ROPI were investigated, demonstrating a correlation between the responsiveness of iPS cell-derived MNs to ROPI and the subjects' clinical response to ROPI. Additionally, a novel mechanism of action involving the inhibition of cholesterol biosynthesis was identified. This study provides a proof-of-concept (PoC) for iPS cell-based drug discovery, and the practical application of ROPI is anticipated following future clinical trials. This can be described as a research achievement that integrates basic and clinical research, which is the essence of Keio's medical sciences.
(Satoru Morimoto, Department of Physiology, Class of 1989 equivalent)
2: Heart-derived collagen promotes maturation of engineered heart tissue
Biomaterials.
2023 August; doi: 10.1016/j.biomaterials.2023.122174
Hidenori Tani, Eiji Kobayashi, Shinomi Yagi, Keisuke Tanaka, Kotaro Kameda-Haga, Shinsuke Shibata, Nobuko Moritoki, Kaworu Takatsuna, Taijun Moriwaki, Otoya Sekine, Tomohiko C Umei, Yuika Morita, Yusuke Soma, Yoshikazu Kishino, Hideaki Kanazawa, Jun Fujita, Shunji Hattori, Keiichi Fukuda, Shugo Tohyama
Cardiomyocytes derived from human iPS cells are a useful cell source for elucidating disease pathology and for drug discovery research, but their immaturity remains a challenge. In this study, as an attempt to mature cardiomyocytes derived from human iPS cells, we focused on the organ-specific extracellular matrix during tissue construction. We extracted collagen from six porcine organs (heart, kidney, spleen, liver, lung, and skin) and created engineered heart tissue from human iPS cells. We found that using heart-derived collagen most effectively promoted structural and functional maturation. As for the mechanism, we clarified that the composition and properties of collagen differ among organs. Heart-derived collagen is rich in type III and type V collagen in addition to type I, and it plays an important role in maintaining the shape and promoting the maturation of myocardial tissue, which continuously contracts and relaxes. These findings are expected to be applied not only to drug discovery and disease model research in the cardiac field but also to the differentiation and maturation induction of other organs and organogenesis research in the future.
(Shugo Tohyama, Department of Cardiology, Class of 1985)
Other Published Papers
1: IASLC Lung Cancer Staging Project: The New Database to Inform Revisions in the Ninth Edition of the TNM Classification of Lung Cancer.
Journal of Thoracic Oncology.
Asamura H, Nishimura KK, Giroux DJ, Chansky K, Hoering A, Rusch V, Rami-Porta R, Comm ISPF, Advisory B, Participating I.