Copper-ATSM as a Treatment for ALS: Support from Mutant SOD1 Models and Beyond

The blood–brain barrier permeant, copper-containing compound, CuII(atsm), has successfully progressed from fundamental research outcomes in the laboratory through to phase 2/3 clinical assessment in patients with the highly aggressive and fatal neurodegenerative condition of amyotrophic lateral sclerosis (ALS). The most compelling outcomes to date to indicate potential for disease-modification have come from pre-clinical studies utilising mouse models that involve transgenic expression of mutated superoxide dismutase 1 (SOD1). Mutant SOD1 mice provide a very robust mammalian model of ALS with high validity, but mutations in SOD1 account for only a small percentage of ALS cases in the clinic, with the preponderant amount of cases being sporadic and of unknown aetiology. As per other putative drugs for ALS developed and tested primarily in mutant SOD1 mice, this raises important questions about the pertinence of CuII(atsm) to broader clinical translation. This review highlights some of the challenges associated with the clinical translation of new treatment options for ALS. It then provides a brief account of pre-clinical outcomes for CuII(atsm) in SOD1 mouse models of ALS, followed by an outline of additional studies which report positive outcomes for CuII(atsm) when assessed in cell and mouse models of neurodegeneration which do not involve mutant SOD1. Clinical evidence for CuII(atsm) selectively targeting affected regions of the CNS in patients is also presented. Overall, this review summarises the existing evidence which indicates why clinical relevance of CuII(atsm) likely extends beyond the context of cases of ALS caused by mutant SOD1.

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Introducing the leapfrog design: A simple Bayesian adaptive rolling trial design for accelerated treatment development and optimization

10.31234/osf.io/zywpr ◽

2018 ◽

Cited By ~ 1

Author(s):

Simon Edward Blackwell ◽

Marcella Woud ◽

Jürgen Margraf ◽

Felix D. Schönbrodt

Keyword(s):

Treatment Options ◽

Science Research ◽

Clinical Translation ◽

Psychological Treatments ◽

Multiple Treatment ◽

Accelerate Development ◽

New Variant ◽

Research Findings ◽

Treatment Research ◽

New Treatment

The application of basic science research to the development and optimization of psychological treatments holds great potential. However, this process of clinical translation is challenging and time-consuming, and the standard route by which it proceeds is inefficient. Adaptive rolling designs, which originated within cancer treatment research, provide an alternative methodology with potential to accelerate development and optimization of psychological treatments. In such designs, multiple treatment options are tested simultaneously, with sequential Bayesian analyses used to remove poorly performing arms. Further, new treatment arms informed by the latest research findings can be introduced into the existing infrastructure as the trial progresses. These features drastically reduce the sample sizes needed and offer a means for more rapid and efficient clinical translation. This paper outlines the utility of such designs to clinical psychological science, focusing on a new variant termed the ‘leapfrog’ design, and discusses their potential uses to accelerate clinical translation.

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Endogenous Cu in the central nervous system fails to satiate the elevated requirement for Cu in a mutant SOD1 mouse model of ALS

Metallomics ◽

10.1039/c6mt00099a ◽

2016 ◽

Vol 8 (9) ◽

pp. 1002-1011 ◽

Cited By ~ 17

Author(s):

J. B. Hilton ◽

A. R. White ◽

P. J. Crouch

Keyword(s):

Central Nervous System ◽

Amyotrophic Lateral Sclerosis ◽

Nervous System ◽

Mouse Model ◽

Limited Capacity ◽

Mutant Sod1 ◽

The Central Nervous System ◽

Sod1 Mouse ◽

Lateral Sclerosis

It is unclear why ubiquitous expression of mutant SOD1 selectively affects the central nervous system in amyotrophic lateral sclerosis. Here we hypothesise that the central nervous system is primarily affected because, unlike other tissues, it has relatively limited capacity to satiate an increased requirement for Cu.

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Dysfunctional mitochondrial Ca2+ handling in mutant SOD1 mouse models of fALS: integration of findings from motor neuron somata and motor terminals

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2014.00184 ◽

2014 ◽

Vol 8 ◽

Cited By ~ 14

Author(s):

Ellen F. Barrett ◽

John N. Barrett ◽

Gavriel David

Keyword(s):

Motor Neuron ◽

Mouse Models ◽

Mutant Sod1 ◽

Sod1 Mouse

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Increased axon initial segment length results in increased Na+ currents in spinal motoneurones at symptom onset in the G127X SOD1 mouse model of Amyotrophic Lateral Sclerosis

10.1101/2020.06.25.096552 ◽

2020 ◽

Author(s):

H. S. Jørgensen ◽

D.B. Jensen ◽

K.P. Dimintiyanova ◽

V.S. Bonnevie ◽

A. Hedegaard ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mouse Models ◽

Symptom Onset ◽

Repetitive Firing ◽

Spinal Motoneurones ◽

Axon Initial Segments ◽

Sod1 Mouse ◽

G93a Sod1 ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disease preferentially affecting motoneurones. Transgenic mouse models have been used to investigate the role of abnormal motoneurone excitability in this disease. Whilst an increased excitability has repeatedly been demonstrated in vitro in neonatal and embryonic preparations from SOD1 mouse models, the results from the only studies to record in vivo from spinal motoneurones in adult SOD1 models have produced conflicting findings. Deficits in repetitive firing have been reported in G93A SOD1 mice but not in presymptomatic G127X SOD1 mice despite shorter motoneurone axon initial segments (AISs) in these mice.These discrepancies may be due to the earlier disease onset and prolonged disease progression in G93A SOD1 mice with recordings potentially performed at a later sub-clinical stage of the disease in this mouse. To test this, and to explore how the evolution of excitability changes with symptom onset we performed in vivo intracellular recording and AIS labelling in G127X SOD1 mice immediately after symptom onset. No reductions in repetitive firing were observed showing that this is not a common feature across all ALS models. Immunohistochemistry for the Na+ channel Nav1.6 showed that motoneurone AISs increase in length in G127X SOD1 mice at symptom onset. Consistent with this, the rate of rise of AIS components of antidromic action potentials were significantly faster confirming that this increase in length represents an increase in AIS Na+ channels occurring at symptom onset in this model.HighightsIn vivo electrophysiological recordings were made in symptomatic G127X SOD1 mice.There were no deficits in repetitive firing in motoneurones in G127X mice.Increased persistent inward currents were still present in the symptomatic mice.Results suggest increases in Na+ currents at axon initial segments (AISs).Immunohistochemistry showed that motoneurone AISs were longer and thinner.

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MicroNeurotrophins Improve Survival in Motor Neuron-Astrocyte Co-Cultures but Do Not Improve Disease Phenotypes in a Mutant SOD1 Mouse Model of Amyotrophic Lateral Sclerosis

PLoS ONE ◽

10.1371/journal.pone.0164103 ◽

2016 ◽

Vol 11 (10) ◽

pp. e0164103 ◽

Cited By ~ 10

Author(s):

Kelly E. Glajch ◽

Laura Ferraiuolo ◽

Kaly A. Mueller ◽

Matthew J. Stopford ◽

Varsha Prabhkar ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Motor Neuron ◽

Mutant Sod1 ◽

Disease Phenotypes ◽

Sod1 Mouse ◽

Lateral Sclerosis

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Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression

Autophagy ◽

10.1080/15548627.2017.1385674 ◽

2017 ◽

Vol 14 (3) ◽

pp. 534-551 ◽

Cited By ~ 27

Author(s):

Nirma D. Perera ◽

Rebecca K. Sheean ◽

Chew L. Lau ◽

Yea Seul Shin ◽

Philip M. Beart ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Disease Progression ◽

Mutant Sod1 ◽

Sod1 Mouse ◽

Lateral Sclerosis

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Ascending neuropathology in the CNS of a mutant SOD1 mouse model of amyotrophic lateral sclerosis

Brain Research ◽

10.1016/j.brainres.2006.04.029 ◽

2006 ◽

Vol 1096 (1) ◽

pp. 180-195 ◽

Cited By ~ 22

Author(s):

Anna Leichsenring ◽

Bettina Linnartz ◽

Xin-Ran Zhu ◽

Hermann Lübbert ◽

Christine C. Stichel

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Mutant Sod1 ◽

Sod1 Mouse ◽

Lateral Sclerosis

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Chemical Library Screening Identifies a Small Molecule That Downregulates SOD1 Transcription for Drugs to Treat Amyotrophic Lateral Sclerosis

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057110397888 ◽

2011 ◽

Vol 16 (4) ◽

pp. 405-414 ◽

Cited By ~ 6

Author(s):

Gaku Murakami ◽

Haruhisa Inoue ◽

Kayoko Tsukita ◽

Yasuyuki Asai ◽

Yuji Amagai ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Dependent Manner ◽

Chemical Library ◽

Mutant Sod1 ◽

Protein Levels ◽

A Cell ◽

High Throughput Assay ◽

Dose Dependent ◽

Sod1 Mutant ◽

Lateral Sclerosis

Familial amyotrophic lateral sclerosis (fALS) accounts for 10% of ALS cases, and about 25% of fALS cases are due to mutations in superoxide dismutase 1 (SOD1). Mutant SOD1-mediated ALS is caused by a gain of toxic function of the mutant protein, and the SOD1 level in nonneuronal neighbors, including astrocytes, determines the progression of ALS (non-cell-autonomous toxicity). Therefore, the authors hypothesized that small molecules that reduce SOD1 protein levels in astrocytes might slow the progression of mutant SOD1-mediated ALS. They developed and optimized a cell-based, high-throughput assay to identify low molecular weight compounds that decrease SOD1 expression transcriptionally in human astrocyte-derived cells. Screening of a chemical library of 9600 compounds with the assay identified two hit compounds that selectively and partially downregulate SOD1 expression in a dose-dependent manner, without any detectable cellular toxicity. Western blot analysis showed that one hit compound significantly decreased the level of endogenous SOD1 protein in H4 cells, with no reduction in expression of β-actin. The assay developed here provides a powerful strategy for discovering novel lead molecules for treating familial SOD1-mediated ALS.

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Introducing the Leapfrog Design: A Simple Bayesian Adaptive Rolling Trial Design for Accelerated Treatment Development and Optimization

Clinical Psychological Science ◽

10.1177/2167702619858071 ◽

2019 ◽

Vol 7 (6) ◽

pp. 1222-1243

Author(s):

Simon E. Blackwell ◽

Marcella L. Woud ◽

Jürgen Margraf ◽

Felix D. Schönbrodt

Keyword(s):

Treatment Options ◽

Science Research ◽

Clinical Translation ◽

Psychological Treatments ◽

Multiple Treatment ◽

Accelerate Development ◽

New Variant ◽

Research Findings ◽

Treatment Research ◽

New Treatment

The application of basic science research to the development and optimization of psychological treatments holds great potential. However, this process of clinical translation is challenging and time-consuming, and the standard route by which it proceeds is inefficient. Adaptive rolling designs, which originated within cancer treatment research, provide an alternative methodology with potential to accelerate development and optimization of psychological treatments. In such designs, multiple treatment options are tested simultaneously, with sequential Bayesian analyses used to remove poorly performing arms. Further, new treatment arms informed by the latest research findings can be introduced into the existing infrastructure as the trial progresses. These features dramatically reduce the sample sizes needed and offer a means for more rapid and efficient clinical translation. This article outlines the utility of such designs to clinical psychological science, focusing on a new variant termed the leapfrog design, and discusses their potential uses to accelerate clinical translation.

Download Full-text