Advances in the Development of Disease-Modifying Treatments for Amyotrophic Lateral Sclerosis

  title={Advances in the Development of Disease-Modifying Treatments for Amyotrophic Lateral Sclerosis},
  author={Diane Moujalled and Anthony R White},
  journal={CNS Drugs},
AbstractAmyotrophic lateral sclerosis (ALS) is a progressive adult-onset, neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. Over recent years, numerous genes ha ve been identified that promote disease pathology, including SOD1, TARDBP, and the expanded hexanucleotide repeat (GGGGCC) within C9ORF72. However, despite these major advances in identifying genes contributing to ALS pathogenesis, there remains only one currently approved therapeutic: the… 

From animal models to human disease: a genetic approach for personalized medicine in ALS

Subgroups of specific ALS-linked gene mutations are used to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease.

Amyotrophic Lateral Sclerosis: Current Therapeutic Perspectives

This chapter focuses on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discusses their impact on disease progression, and summarizes the progress in the non-pharmacological therapy trials in ALS.

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

Almost 2 decades of research in the field is reviewed, first highlighting the steps required to efficiently generate MNs from human ESCs and iPSCs that led to the identification of compounds currently being tested in clinical trials for ALS and discussing the potential and caveats of using patient iPSC-derived MNs as a platform for drug screening.

Amyotrophic Lateral Sclerosis Modifiers in Drosophila Reveal the Phospholipase D Pathway as a Potential Therapeutic Target

Two independent genome-wide screens for modifiers of degenerative phenotypes associated with the expression of transgenic constructs carrying familial ALS-causing alleles of FUS (hFUSR521C) and TDP-43 (hTDP- 43M337V) uncover a complex array of genes affecting either or both of the two strains.

Exploring the genetics and non-cell autonomous mechanisms underlying ALS/FTLD

How recent genetic studies have bridged the mechanistic understanding of these two related diseases is surveyed and how the genetics behind ALS and FTLD point to complex disorders, implicating non-neuronal cell types in disease pathophysiology is surveyed.

Novel therapies in development that inhibit motor neuron hyperexcitability in amyotrophic lateral sclerosis

A trial of a K+ channel activator (retigabine) is underway, while edaravone is currently being considered for licensing by drug approval agencies based on a hypothesis that the elimination of free radicals may lead to protection of motor neurones.

Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis

These findings implicate immunosenescence and metabolism as novel targets for biomarkers and therapeutic discovery and suggest immunomodulation as an early intervention.

Systems Biology of RNA-Binding Proteins in Amyotrophic Lateral Sclerosis

This chapter begins by summarizing the ALS and involvement of RBPs, and provides a comprehensive overview of applications of systems biology to study ALS, imagining that the integration of highly efficient computational tools with multiple omic analyses will help in the discovery of new therapeutic interventions in ALS.



Mechanisms, models and biomarkers in amyotrophic lateral sclerosis

Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery.

Rodent Models of Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the central nervous system. Patients with ALS develop extensive muscle wasting and atrophy

SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments

The SOD1 and TDP-43 animal models created to date are summarised, report on recent findings supporting the potential mechanisms of ALS pathogenesis, and correlate this understanding with current developments in the clinic.

A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis

The slowly progressive pathology observed in this mouse strain could provide a more appropriate model for studying early-stage pathological processes in ALS and aid the development of therapies forEarly-stage treatments.

Minocycline Slows Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis

Results indicate that minocycline, which is clinically well tolerated, may represent a novel and effective drug for treatment of ALS.

The non-cell-autonomous component of ALS: new in vitro models and future challenges.

The advent of induced pluripotent stem cell (iPSC) technology and the newly developed induced neural progenitor cells (iNPCs) have created unprecedented exciting opportunities to unravel the mechanisms involved in neurodegeneration and initiate high-throughput drug screenings.

Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis

Ongoing research on the cellular pathways highlighted in this Review is predicted to open the door to new therapeutic interventions to slow disease progression in ALS.

Genetics of amyotrophic lateral sclerosis: an update

This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the disease neuropathogenesis.

TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration

The results indicate that the cellular and molecular substrates for selective vulnerability in FTLD-U and ALS are shared between mice and humans, and suggest that altered DNA/RNA-binding protein function, rather than toxic aggregation, is central to TDP-43-related neurodegeneration.