Amyotrophic Lateral Sclerosis (ALS) Drug Discovery Service

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Overview

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor pathways that inevitably leads to death within a few years of onset. The discovery of hexanucleotide repeat expansions in C9orf72 is the major genetic cause of ALS and frontotemporal dementia proves that these disorders can be extremes on the phenotypic spectrum of a single disease, meaning that ALS is a neurodegenerative disease rather than a neuromuscular disease. Traditionally, ALS has been classified as either a sporadic or familial form.

In Vitro and In Vivo Models of ALS

To identify new therapeutic targets for ALS, it is necessary to better understand the disease mechanisms that lead to motor neuron (MN) degeneration. To investigate these mechanisms, researchers are modeling certain aspects of ALS in a range of model systems. Such model systems vary from in vitro biochemical systems, to cell culture systems, invertebrates, non-mammalian vertebrates, and extend to rodent models, and more recently, to human patient-derived stem cell models. The ability to study cellular molecular processes, identify key pathways for intervention, and assess multiple candidate therapies over short periods, depends on the development of disease models.

• Cellular Systems

Many of the genetic mutations associated with ALS cause the production of abnormal proteins. In vitro oligomer and aggregation experiments help us to understand the biophysical principles of protein aggregation. Various cell lines have been used to study the function of genes associated with ALS or toxicity associated with the overexpression of wild-type or mutant proteins.

• Small-animal and Rodent Models

Genetic mutations present in rodent models are most common in ALS patients and are widely used to study disease mechanisms. Although rodent models are considered the gold standard for validating disease mechanisms and for providing preclinical data on potential therapeutic targets, small-animal models are increasingly being used to model the diverse genetic causes of ALS. They can be generated quickly, are cheap to maintain relative to rodent models, and are amenable to genetic or compound screening.

Fig.1 Model systems in ALS research. (Van, et al., 2017)

ALS Biomarker Assay

Finding reliable biomarkers is the priority of ALS research. Diagnostic biomarkers could reduce diagnostic delay and would facilitate early initiation of treatment, which is probably when treatment of a neurodegenerative disease is most effective. Given that ALS affects both upper and lower motor neurons as well as the frontal and temporal lobes, different diseases may require different biomarkers. The ideal biomarker would be reliable and simple to measure.

ALS Disease Mechanism of Action (MoA)

Diverse genetic approaches have enabled rapid dissection of the complex genetic and cellular events that underlie the initiation and progression of motoneuron death in ALS. SOD1 is a cytosolic enzyme that catalyzes the detoxification of superoxide, but missense mutations in SOD1 do not seem to cause ALS by a loss of dismutase activity. Instead, a toxic gain-of-function is thought to underlie the disease-associated role of this protein. TDP-43 and FUS are RNA- and DNA-binding proteins that play a role in numerous cellular processes, including transcription, splicing, microRNA maturation, RNA transport, and stress granule formation. The nuclear loss of TDP-43 and FUS function, their cytoplasmic aggregation, and aggregate-associated cytotoxicity are believed to contribute to ALS pathogenesis. The rapid discovery of genes has promoted the study of molecular biology, and there are now many different ALS gene models. Studying these disease models has pinpointed potential therapeutic targets.

Creative Biolabs provides one-stop solutions for ALS research that may lead to a better understanding of ALS, advance ALS research, and develop promising new therapies. If you are interested in our ALS solutions, please feel free to contact us for more.

Reference

1. Van, D.P.; et al. Modelling amyotrophic lateral sclerosis: progress and possibilities. Disease Models & Mechanisms. 2017, 10(5): 537-549.