scholarly journals Advances in toponomics drug discovery: Imaging cycler microscopy correctly predicts a therapy method of amyotrophic lateral sclerosis

2015 ◽  
Vol 87 (8) ◽  
pp. 696-703 ◽  
Author(s):  
Walter Schubert
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Drug Discovery ◽  
Lateral Sclerosis

Simple animal models for amyotrophic lateral sclerosis drug discovery

2016 ◽  
Vol 11 (8) ◽  
pp. 797-804 ◽  
Author(s):  
Shunmoogum A. Patten ◽  
J. Alex Parker ◽  
Xiao-Yan Wen ◽  
Pierre Drapeau
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Drug Discovery ◽  
Animal Models ◽  
Lateral Sclerosis

scholarly journals 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

2021 ◽  
Vol 1 ◽  
Author(s):  
Nuno Jorge Lamas ◽  
Laurent Roybon
Keyword(s):  
Stem Cells ◽  
Amyotrophic Lateral Sclerosis ◽  
Drug Discovery ◽  
Animal Models ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Embryonic Stem ◽  
Patient Specific ◽  
Human Escs ◽  
Lateral Sclerosis

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.

scholarly journals Specific biosensors in drug discovery for Amyotrophic Lateral Sclerosis

Dianas ◽  
2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Carlota Tosat-Bitrián ◽  
Ana Martínez ◽  
Valle Palomo
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Drug Discovery ◽  
Lateral Sclerosis

scholarly journals Combined Analysis of Phenotypic and Target-Based Screening in Assay Networks

2014 ◽  
Vol 19 (5) ◽  
pp. 782-790 ◽  
Author(s):  
S. Joshua Swamidass ◽  
Constantino N. Schillebeeckx ◽  
Matthew Matlock ◽  
Mark R. Hurle ◽  
Pankaj Agarwal
Keyword(s):  
Cell Death ◽  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Drug Discovery ◽  
Small Molecule ◽  
Global Analysis ◽  
New Drugs ◽  
Biologic Drugs ◽  
Interactive Version ◽  
Lateral Sclerosis

Small-molecule screens are an integral part of drug discovery. Public domain data in PubChem alone represent more than 158 million measurements, 1.2 million molecules, and 4300 assays. We conducted a global analysis of these data, building a network of assays and connecting the assays if they shared nonpromiscuous active molecules. This network spans both phenotypic and target-based screens, recapitulates known biology, and identifies new polypharmacology. Phenotypic screens are extremely important for drug discovery, contributing to the discovery of a large proportion of new drugs. Connections between phenotypic and biochemical, target-based screens can suggest strategies for repurposing both small-molecule and biologic drugs. For example, a screen for molecules that prevent cell death from a mutated version of superoxide-dismutase is linked with ALOX15. This connection suggests a therapeutic role for ALOX15 inhibitors in amyotrophic lateral sclerosis. An interactive version of the network is available online ( http://swami.wustl.edu/flow/assay_network.html ).

Automated Acoustic Analysis of Oral Diadochokinesis to Assess Bulbar Motor Involvement in Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 63 (1) ◽  
pp. 59-73 ◽  
Author(s):  
Panying Rong
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Acoustic Analysis ◽  
Speaking Rate ◽  
Disease Stage ◽  
Healthy Controls ◽  
Tongue Movement ◽  
Major Barrier ◽  
Syllable Repetition ◽  
Oral Diadochokinesis ◽  
Lateral Sclerosis

Purpose The purpose of this article was to validate a novel acoustic analysis of oral diadochokinesis (DDK) in assessing bulbar motor involvement in amyotrophic lateral sclerosis (ALS). Method An automated acoustic DDK analysis was developed, which filtered out the voice features and extracted the envelope of the acoustic waveform reflecting the temporal pattern of syllable repetitions during an oral DDK task (i.e., repetitions of /tɑ/ at the maximum rate on 1 breath). Cycle-to-cycle temporal variability (cTV) of envelope fluctuations and syllable repetition rate (sylRate) were derived from the envelope and validated against 2 kinematic measures, which are tongue movement jitter (movJitter) and alternating tongue movement rate (AMR) during the DDK task, in 16 individuals with bulbar ALS and 18 healthy controls. After the validation, cTV, sylRate, movJitter, and AMR, along with an established clinical speech measure, that is, speaking rate (SR), were compared in their ability to (a) differentiate individuals with ALS from healthy controls and (b) detect early-stage bulbar declines in ALS. Results cTV and sylRate were significantly correlated with movJitter and AMR, respectively, across individuals with ALS and healthy controls, confirming the validity of the acoustic DDK analysis in extracting the temporal DDK pattern. Among all the acoustic and kinematic DDK measures, cTV showed the highest diagnostic accuracy (i.e., 0.87) with 80% sensitivity and 94% specificity in differentiating individuals with ALS from healthy controls, which outperformed the SR measure. Moreover, cTV showed a large increase during the early disease stage, which preceded the decline of SR. Conclusions This study provided preliminary validation of a novel automated acoustic DDK analysis in extracting a useful measure, namely, cTV, for early detection of bulbar ALS. This analysis overcame a major barrier in the existing acoustic DDK analysis, which is continuous voicing between syllables that interferes with syllable structures. This approach has potential clinical applications as a novel bulbar assessment.

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