Induced pluripotent stem cells-based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis.
amyotrophic lateral sclerosis (ALS)
clinical trials
induced pluripotent stem cell (iPSC)
motor neurons (MNs)
ropinirole hydrochloride (ROPI)
sterol regulatory element-binding protein 2 (SREBP2)
Journal
Journal of neurochemistry
ISSN: 1471-4159
Titre abrégé: J Neurochem
Pays: England
ID NLM: 2985190R
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
revised:
09
10
2023
received:
27
07
2023
accepted:
19
10
2023
medline:
7
12
2023
pubmed:
13
11
2023
entrez:
12
11
2023
Statut:
ppublish
Résumé
It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs-based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs-based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS-specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double-blind, randomized, placebo-controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient-derived iPSCs-motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA-seq data showed that ROPI treatment suppressed the sterol regulatory element-binding protein 2-dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.
Substances chimiques
ezogabine
12G01I6BBU
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
603-614Subventions
Organisme : Japan Agency for Medical Research and Development
ID : JP21wm0425009
Organisme : Japan Agency for Medical Research and Development
ID : JP22bm0804003
Organisme : Japan Agency for Medical Research and Development
ID : JP22ek0109616
Organisme : Japan Agency for Medical Research and Development
ID : JP23bm1423002
Organisme : Japan Agency for Medical Research and Development
ID : JP23bm1123046
Organisme : Japan Agency for Medical Research and Development
ID : JP23kk0305024
Organisme : Japan Society for the Promotion of Science
ID : JP20H00485
Organisme : Japan Society for the Promotion of Science
ID : JP21H05278
Organisme : Japan Society for the Promotion of Science
ID : JP22K15736
Organisme : Japan Society for the Promotion of Science
ID : JP22K07500
Informations de copyright
© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.
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