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Title [sv]
Om orsakerna till Amyotrofisk lateral skleros (ALS): Translationell klinisk-genetisk forskning om ALS med eller utan demens: Hämning av SOD1 som ny effektiv behandling av ALS
Title [en]
On the Origin of ALS: Clinical-genetic research into the etiology of ALS with or without dementia: Translation into Inhibition of SOD1 prion as a novel new intervention for treating ALS
Abstract [en]
ALS is a fatal degenerative syndrome hallmarked by progressive wasting of skeletal muscles through motor neuron degeneration. The median survival time is 3 years. Genetic studies have identified 36 genes to cause ALS. Most common are mutations in C9orf72, SOD1 and TBK1 (in 14%, 6%, 3% of Swedish patients). There is genotypic and phenotypic heterogeneity including comorbidity with other conditions, in particular FTD. We have shown that spinal injection of misfolded SOD1 protein in mice elicit a murine ALS disease suggesting that ALS is a prionic syndrome. All our autopsied ALS and FTD patients have irrespectively of genotype neuronal inclusions of misfolded SOD1 species with a similar distribution pattern as observed in our SOD1-transgenic mice models. These findings suggest that SOD1 is a key player in all types of ALS.Aims: (1) to search for ALS-causing genes, (2) to search for neuroprotective genetic variants and (3) develop and clinically test strategies to reduce SOD1 in patients.How: (1), (2) We will perform whole genome sequencing in 1,000 Swedish patients to identify novel predisposing genes for ALS as well as modifier genes influencing disease onset, progression and phenotype.(3) To reduce SOD1 we will perform clinical trials using pyrimethamine, the HSP-inducer arimoclomol, antisense oligonucleotides targeting SOD1 mRNA (initiated). In our pipeline are studies using antibodies specific for misfolded SOD1 species and AAV9 vectors with siRNA to silence mutant genes.
Principal InvestigatorAndersen, Peter
Coordinating organisation
Umeå University
Funder
Period
2018-01-01 － 2022-12-31
National Category
NeurosciencesMedical GeneticsNeurology
Identifiers
DiVA, id: project:1531Project, id: 2017-03100_VR

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