Clinical trials in amyotrophic lateral sclerosis (ALS) are challenged by the lack of pre-clinical models and biomarkers of disease onset and progression. In this issue, Morimoto et al. use induced pluripotent stem cell (iPSC)-derived motor neurons from patients with ALS to study therapeutic mechanisms of ropinirole in a clinical trial and identify treatment responders.
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How is Excitotoxicity Being Modelled in iPSC-Derived Neurons?
Neurotox Res
October 2024
Wicking Dementia Research and Education Centre, College of Health and Medicine, University of Tasmania, 17 Liverpool Street, Hobart, TAS, Australia.
Article Synopsis
- Excitotoxicity, linked to environmental factors and neuronal hyperexcitability, is a key mechanism in the neurodegeneration seen in ALS (amyotrophic lateral sclerosis).
- Animal models and advances in induced pluripotent stem cell (iPSC) technologies have allowed researchers to study excitotoxic mechanisms in a more human-relevant context, facilitating the exploration of gene-environment interactions.
- The review emphasizes the importance of understanding neurotransmitter receptor expressions in iPSC-derived neurons, as well as new methods for inducing and studying excitotoxicity to better grasp the pathological processes involved in ALS.
Background: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood.
View Article and Find Full Text PDFThe necessity to improve disaster preparedness among patients with amyotrophic lateral sclerosis and their families.
J Clin Neurosci
October 2023
Department of Neurology, Toho University Faculty of Medicine, 5-21-16 Omorinishi, Ota-ku, Tokyo 143-8540, Japan. Electronic address:
Disaster preparation is an important issue for patients with amyotrophic lateral sclerosis (ALS). However, to the best of our knowledge, no studies have investigated disaster preparedness among patients with ALS. In this study, we aimed to investigate disaster preparation in patients with ALS and their caregivers, including their families, in Japan.
View Article and Find Full Text PDFA scalable human iPSC-based neuromuscular disease model on suspended biobased elastomer nanofiber scaffolds.
Biofabrication
September 2023
Centre for Gene Therapy & Regenerative Medicine, Faculty of Life Sciences & Medicine, King's College London, London SE1 9RT, United Kingdom.
Many devastating neuromuscular diseases currently lack effective treatments. This is in part due to a lack of drug discovery platforms capable of assessing complex human neuromuscular disease phenotypes in a scalable manner. A major obstacle has been generating scaffolds to stabilise mature contractile myofibers in a multi-well assay format amenable to high content image (HCI) analysis.
View Article and Find Full Text PDFPhase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery.
Cell Stem Cell
June 2023
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address:
Article Synopsis
- iPSC-based drug discovery led to a clinical trial investigating ropinirole for treating sporadic ALS, involving 20 participants over 24 weeks to assess safety and effects.
- The results showed that while muscle strength and daily activities were stable, the primary functional measure (ALSFRS-R) did not significantly improve compared to the placebo group during the double-blind period.
- In an open-label extension, the ropinirole group demonstrated a significant slowdown in ALSFRS-R decline and extended disease-progression-free survival, but the study faced challenges like small sample size and participant dropouts, necessitating further research.
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