Induced pluripotent stem cells‐based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis

Abstract

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.

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

“…There has recently been renewed efforts in the development of therapeutics for ALS [ 216 ] invoking the potential role of mitochondria [ 217 ] and the gut–brain axis [ 218 ], as well as anti-sense therapies [ 219 ] and personalized immunotherapy [ 220 ]. Future efforts to better understand the pathogenesis of ALS and screen for effective treatments will use human organoids composed of iPSC [ 221 , 222 ] discussed in the last section.…”

Establishment of a novel amyotrophic lateral sclerosis patient-derived blood-brain barrier model: Investigating barrier dysfunction and immune cell interaction

“…We have recently established the method called extended endothelial cell culture method (EECM) for differentiating BMEC-like cells from human induced pluripotent stem cells (hiPSCs) and investigated the role of the BBB in pathological conditions(Nishihara et al, 2020; Nishihara et al, 2021; Matsuo et al, 2023). Previous studies and reviews reported that hiPSC models reflect human disease pathophysiology, therapeutic effect, and clinical condition of patients (Okano et al, 2020; Okano and Morimoto, 2022; Morimoto et al, 2023; Okano et al, 2023). Widely used differentiation methods for BMEC-like cells(Lippmann et al, 2012; Qian et al, 2017) show a robust diffusion barrier and expression of several BMEC-specific transporters but have some limitations.…”

Table1.DOCX

“…To bridge the gap, in vitro models have been developed as recently reviewed (Zhou et al, 2023). Human induced pluripotent stem cells (hiPSC) can be exploited for a deeper understanding of developmental biology, disease modeling, and testing of drugs or therapeutic efficiency (Okano et al, 2023) and are therefore valuable tools for addressing ALS pathogenesis. Pioneered by Takahashi and Yamanaka (Takahashi and Yamanaka, 2006), iPSC technology has experienced rapid development, eliciting hiPSC determination towards various lineages.…”