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ALS Disease Study

Identifying novel targets with genetic linkage to stratified patient subgroups

>30

novel ALS risk-associated genes identified

9

druggable targets selected, each representing a different novel mechanism

5/9

compounds demonstrated potential for improving motor neurone survival 

Overview

ALS, also known as motor neurone disease (MND) or Lou Gherig’s disease, is a progressive, fatal neurological disease characterized by degenerative changes in upper and lower motor neurons, resulting in loss of muscle control. There are no effective therapies. Our study analyzed genetic and clinical data from 1,386 ALS patients against healthy matched controls.

For the first time, we were able to stratify ALS patients into siz clinically relevant subgroups based on their genetic differences.

This study rapidly generated novel disease insights that can't be seen using other analysis methods.

Background

Amyotrophic lateral sclerosis is usually diagnosed between the ages of 40-70. It is characterized by a peripheral neuropathy that migrates centrally and disease causes, symptoms and progression vary greatly. There is no cure for the disease and there are only two approved therapies, which have limited efficacy.

ALS affects approximately one in every 100,000 people1. Patients have a mean survival from onset of symptoms of 3–5 years, with outlier cases of 12–18 months or up to 10 years2. ALS can be classified into several different subtypes, often depending on the site of onset of neurodegeneration. These include primary lateral sclerosis (PLS), which affects the upper motor neurones, progressive bulbar palsy (PBP), which targets patients’ speaking, swallowing, and mouth function, and progressive muscular atrophy (PMA), which causes deterioration of the lower motor neurones first3. These subtypes all have different characteristics, including differential disease progression rates and severity, as well as age of onset and death4. The genetic causes of each of these subtypes and the reasons for differing prognoses were unclear when we ran our study.

We used our unique combinatorial approach to identify novel risk-associated genes in two ALS cohorts, and clustered these cohorts based on their genetic signatures. This was designed to reveal new genetic insights into the underlying causes of different ALS subtypes and varying disease progression rates.

Outcomes

Novel druggable targets for clinically relevant ALS subgroups

Our combinatorial analytics identified >30 risk-associated genes that were highly associated with ALS cases. Biological analysis of the genes revealed that many have a plausible mechanistic connection to the regulation of neurodegenerative disease processes. When patients were clustered by their genetic variants, we identified three distinct patient clusters in each cohort.

This analysis demonstrates that our combinatorial analytics approach is able to identify novel risk-associated genes and druggable targets, and stratify patients into clinically relevant subgroups based on their genetic differences, even in such a complex and heterogeneous disease as ALS.

ALS Disease Architecture

73
disease risk loci (SNPs)
>30
risk-associated genes mapped to disease-associated mechanisms
16
druggable targets
19
tool compounds
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ALS

Collaborators

ProjectMinE-logo

Project MinE

PrecisionLife used genetic data from 1,386 UK
amyotrophic lateral sclerosis (ALS) patients found
in the Project MinE dataset.

MNDA-logo

Motor Neurone Disease Association

Clinical and phenotypic data was provided for 1,386 of these genotyped ALS patients by the Motor Neurone Disease Association (MNDA). 

References

  1. GBD 2016 Motor Neuron Disease Collaborators (2018). Global, regional, and national burden of motor neuron diseases 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet. Neurology, 17(12), 1083–1097. https://doi.org/10.1016/S1474- 4422(18)30404-6

  2. Chiò, A., Logroscino, G., Hardiman, O., Swingler, R., Mitchell, D., Beghi, E., Traynor, B. G., & Eurals Consortium (2009). Prognostic factors in ALS: A critical review. Amyotrophic Lateral Sclerosis, 10(5–6), 310–323. https:// doi.org/10.3109/17482960802566824

  3. Turner, M. R., & Swash, M. (2015). The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey. Journal of Neurology, Neurosurgery, and Psychiatry, 86(6), 667–673. https://doi.org/10.1136/jnnp-2014-308946

  4. Nowicka, N., Juranek, J., Juranek, J. K., & Wojtkiewicz, J. (2019). Risk Factors and Emerging Therapies in Amyotrophic Lateral Sclerosis. International Journal of Molecular Sciences, 20(11), 2616. https://doi.org/10.3390/ijms20112616

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