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Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Drug Repositioning
Stefania Olla1, Maristella Steri1, Alessia Formato2
1Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042 Monserrato, Italy.
Abstract:
In multiple sclerosis (MS), oxidative stress (OS) is implicated in the neurodegenerative processes that occur from the beginning of the disease. Unchecked OS initiates a vicious circle caused by its crosstalk with inflammation, leading to demyelination, axonal damage and neuronal loss. The failure of MS antioxidant therapies relying on the use of endogenous and natural compounds drives the application of novel approaches to assess target relevance to the disease prior to preclinical testing of new drug candidates. To identify drugs that can act as regulators of intracellular oxidative homeostasis, we applied an in silico approach that links genome-wide MS associations and molecular quantitative trait loci (QTLs) to proteins of the OS pathway. We found 10 drugs with both central nervous system and oral bioavailability, targeting five out of the 21 top-scoring hits, including arginine methyltransferase (CARM1), which was first linked to MS. In particular, the direction of brain expression QTLs for CARM1 and protein kinase MAPK1 enabled us to select BIIB021 and PEITC drugs with the required target modulation. Our study highlights OS-related molecules regulated by functional MS variants that could be targeted by existing drugs as a supplement to the approved disease-modifying treatments.
Insights
This study identifies existing drugs that can target oxidative stress (OS) in multiple sclerosis (MS). These drugs may help regulate cellular balance and offer new therapeutic avenues for MS patients.
Area of Science:
- Neuroimmunology
- Pharmacology
- Genetics
Background:
- Oxidative stress (OS) is a key driver of neurodegeneration in multiple sclerosis (MS), contributing to inflammation, demyelination, and neuronal loss.
- Existing antioxidant therapies for MS have shown limited success, necessitating novel approaches to identify therapeutic targets.
- Understanding the interplay between OS and genetic factors in MS is crucial for developing effective treatments.
Purpose of the Study:
- To identify existing drugs that can modulate intracellular oxidative homeostasis in the context of multiple sclerosis.
- To link genome-wide MS associations and molecular quantitative trait loci (QTLs) to proteins within the oxidative stress pathway.
- To discover novel therapeutic targets for MS by analyzing OS-related molecules influenced by genetic variants.
Main Methods:
- An in silico approach was employed, integrating genome-wide MS association data with molecular QTLs.
- Proteins within the oxidative stress pathway were analyzed for their relevance to MS.
- Drug candidates with central nervous system and oral bioavailability were screened for their ability to target identified MS-associated genes.
Main Results:
- Ten drugs were identified with both central nervous system and oral bioavailability, targeting five key genes in the OS pathway.
- Arginine methyltransferase (CARM1) was identified as a novel gene linked to MS through this approach.
- Specific drugs, BIIB021 and PEITC, were selected for their ability to modulate CARM1 and MAPK1 based on brain expression QTLs.
Conclusions:
- The study highlights OS-related molecules regulated by functional MS variants as potential therapeutic targets.
- Existing drugs targeting these OS pathways could serve as supplementary treatments for MS.
- This approach provides a framework for repurposing drugs and identifying novel therapeutic strategies for multiple sclerosis.
