Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation

Huang, Xuan; Roet, Kasper C.D.; Zhang, Liying; Brault, Amy; Berg, Allison P.; Jefferson, Anne B.; Klug-McLeod, Jackie; Leach, Karen L.; Vincent, Fabien; Yang, Hongying; Coyle, Anthony J.; Jones, Lyn H.; Frost, Devlin; Wiskow, Ole; Chen, Kuchuan; Maeda, Rie; Grantham, Alyssa; Dornon, Mary Kate; Klim, Joseph R.; Siekmann, Marco T.; Zhao, Dongyi; Lee, Seungkyu; Eggan, Kevin; Woolf, Clifford J.

doi:10.1016/j.celrep.2021.109224

Cited by 39 publications

(28 citation statements)

References 64 publications

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“…The first of these therapeutic clinical candidates, identified in 2015, was the Kv7 channel activator Retigabine/Ezogabine, a known anti-epileptic drug (Wainger et al, 2014;Wainger et al, 2020). Neuronal hyperexcitability is a significant pathophysiological mechanism in ALS (Vucic et al, 2008;Fogarty, 2018;Huang et al, 2021). Through electrophysiological analysis using multielectrode arrays, the Eggan team demonstrated that Retigabine/Ezogabine was capable of suppressing the hyperexcitability of ALS iPSCderived MNs (Wainger et al, 2014).…”

Section: Using Human Motor Neurons Generated From Pluripotent Stem Cells To Perform In Vitro Drug Testingmentioning

confidence: 99%

“…The positive action of Ropinirole in ALS MNs is not fully understood yet, but it was proposed to be linked with the reduction of toxic neuronal hyperexcitability via Dopamine D2R activation (Okano et al, 2020). Other studies have also recently identified D2 dopamine receptors as significant modulators of ALS MN excitability (Huang et al, 2021). Interestingly, the beneficial effects of Ropinirole were also identified in non-SOD1 sALS MNs, but not in SOD1-mutant ALS models (Fujimori et al, 2018).…”

Section: Using Human Motor Neurons Generated From Pluripotent Stem Cells To Perform In Vitro Drug Testingmentioning

confidence: 99%

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Harnessing the Potential of Human Pluripotent Stem Cell-Derived Motor Neurons for Drug Discovery in Amyotrophic Lateral Sclerosis: From the Clinic to the Laboratory and Back to the Patient

Lamas

Roybon

2021

Front. Drug. Discov.

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Amyotrophic Lateral Sclerosis (ALS) is a motor neurodegenerative disorder whose cellular hallmarks are the progressive death of motor neurons (MNs) located in the anterior horn of the spinal cord, brainstem and motor cortex, and the formation of intracellular protein aggregates. Over the course of the disease, progressive paralysis takes place, leading to patient death within 3–5 years after the diagnosis. Despite decades of intensive research, only a few therapeutic options exist, with a limited benefit on the disease progression. Preclinical animal models have been very useful to decipher some aspects of the mechanisms underlying ALS. However, discoveries made using transgenic animal models have failed to translate into clinically meaningful therapeutic strategies. Thus, there is an urgent need to find solutions to discover drugs that could impact on the course of the disease, with the ultimate goal to extend the life of patients and improve their quality of life. Induced pluripotent stem cells (iPSCs), similarly to embryonic stem cells (ESCs), have the capacity to differentiate into all three embryonic germ layers, which offers the unprecedented opportunity to access patient-specific central nervous system cells in an inexhaustible manner. Human MNs generated from ALS patient iPSCs are an exciting tool for disease modelling and drug discovery projects, since they display ALS-specific phenotypes. Here, we attempted to review almost 2 decades of research in the field, first highlighting the steps required to efficiently generate MNs from human ESCs and iPSCs. Then, we address relevant ALS studies which employed human ESCs and iPSC-derived MNs that led to the identification of compounds currently being tested in clinical trials for ALS. Finally, we discuss the potential and caveats of using patient iPSC-derived MNs as a platform for drug screening, and anticipate ongoing and future challenges in ALS drug discovery.

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Section: Using Human Motor Neurons Generated From Pluripotent Stem Cells To Perform In Vitro Drug Testingmentioning

confidence: 99%

Section: Using Human Motor Neurons Generated From Pluripotent Stem Cells To Perform In Vitro Drug Testingmentioning

confidence: 99%

Harnessing the Potential of Human Pluripotent Stem Cell-Derived Motor Neurons for Drug Discovery in Amyotrophic Lateral Sclerosis: From the Clinic to the Laboratory and Back to the Patient

Lamas

Roybon

2021

Front. Drug. Discov.

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“…Another recent study used a chemogenomic library of 2899 compounds, 67 of which reduced the hyperexcitability of ALS motor neurons carrying the SOD1(A4V) mutation. The targets include two known ALS excitability modulators, AMPA receptors, Kv7.2/3 ion channels, and D2 dopamine receptors as modulators [ 210 ]. These studies provide evidence for the successful use of hiPSCs for screening or existing drugs for advancement to clinical trials for the potential treatment of ALS.…”

Section: Disease Modeling Using Hipscsmentioning

confidence: 99%

Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases

Trudler

Ghatak

Lipton

2021

IJMS

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Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.

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“…C9ORF72 RE motor neurons also demonstrated an increase in the expression of SK channel subunits, which could be corrected using specific inhibition of the SRSF1-dependent nuclear export of pathological C9ORF72 RE transcripts ( Castelli et al, 2021 ). Contrastingly, hyperexcitability in lower motor neurons has been established in several other ALS models and studies have used pharmacological activators of Kv7 potassium ion channels to reduce hyperexcitability in C9ORF72 RE -derived motor neurons with the possibility that they protect motor neurons from excitotoxicity ( Wainger et al, 2014 ; Huang et al, 2021 ). These studies have now been translated into clinical trials ( Wainger et al, 2021 ).…”

Section: Lower Motor Neuron Dysfunction In C9orf72 Re -Mediated Amyotrophic Lateral Sclerosis- Frontotempormentioning

confidence: 99%

Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

Pasniceanu

Atwal

Souza

et al. 2021

Front. Cell. Neurosci.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by degeneration of upper and lower motor neurons and neurons of the prefrontal cortex. The emergence of the C9ORF72 hexanucleotide repeat expansion mutation as the leading genetic cause of ALS and FTD has led to a progressive understanding of the multiple cellular pathways leading to neuronal degeneration. Disturbances in neuronal function represent a major subset of these mechanisms and because such functional perturbations precede degeneration, it is likely that impaired neuronal function in ALS/FTD plays an active role in pathogenesis. This is supported by the fact that ALS/FTD patients consistently present with neurophysiological impairments prior to any apparent degeneration. In this review we summarize how the discovery of the C9ORF72 repeat expansion mutation has contributed to the current understanding of neuronal dysfunction in ALS/FTD. Here, we discuss the impact of the repeat expansion on neuronal function in relation to intrinsic excitability, synaptic, network and ion channel properties, highlighting evidence of conserved and divergent pathophysiological impacts between cortical and motor neurons and the influence of non-neuronal cells. We further highlight the emerging association between these dysfunctional properties with molecular mechanisms of the C9ORF72 mutation that appear to include roles for both, haploinsufficiency of the C9ORF72 protein and aberrantly generated dipeptide repeat protein species. Finally, we suggest that relating key pathological observations in C9ORF72 repeat expansion ALS/FTD patients to the mechanistic impact of the C9ORF72 repeat expansion on neuronal function will lead to an improved understanding of how neurophysiological dysfunction impacts upon pathogenesis.

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Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation

Cited by 39 publications

References 64 publications

Harnessing the Potential of Human Pluripotent Stem Cell-Derived Motor Neurons for Drug Discovery in Amyotrophic Lateral Sclerosis: From the Clinic to the Laboratory and Back to the Patient

Harnessing the Potential of Human Pluripotent Stem Cell-Derived Motor Neurons for Drug Discovery in Amyotrophic Lateral Sclerosis: From the Clinic to the Laboratory and Back to the Patient

Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases

Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

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