Unlocking Neuroprotection in MS: Genetics Points to Existing Drugs That Fight Oxidative Stress
Multiple Sclerosis (MS) is a debilitating complex immune-mediated neurodegenerative disease of the central nervous system (CNS). It primarily affects young adults, leading to demyelination and neuronal loss. While current immunomodulatory therapies are effective in the early stages, they largely fail to prevent the disease from progressing into a phase defined by the accumulation of neuronal damage. This creates an urgent need for agents capable of slowing neurodegeneration and disability progression.
A major culprit in the ongoing damage seen in MS is Oxidative Stress (OS).
The Vicious Cycle of Oxidative Stress in MS
In MS, OS is deeply involved in neurodegenerative processes right from the start of the disease. Neuroinflammation—a key factor in MS pathogenesis—involves the production of inflammatory molecules, including reactive oxygen species (ROS) and reactive nitrogen species (RNS).
When the generation of these reactive species (like superoxide ions, hydrogen peroxide, and nitric oxide) overwhelms the body’s antioxidant defense systems, the resulting oxidative/nitrosative stress initiates a vicious cycle. This sustained inflammatory phase damages lipids, proteins, and nucleic acids, ultimately causing demyelination, axonal damage, and cell death in the CNS tissue.
Although the importance of OS is clear, most complementary antioxidant therapies based on endogenous and natural compounds have failed in MS clinical evaluations. This failure suggests that traditional small molecules acting merely as scavengers were based on an incomplete understanding of antioxidant defense processes during the disease.
A Smart Solution: Drug Repositioning via Genetics
To overcome these challenges, researchers sought a novel approach: identifying drugs that can act as effective regulators of intracellular oxidative homeostasis. The strategy relies on drug repositioning, a computational search for existing drugs that modulate molecular targets identified by genetic studies, which significantly reduces the costs and timescales of drug development.
The authors of this study designed an integrated in silico (computational) workflow that combined:
1. Human Genetics of MS (from Genome-Wide Association Studies, GWAS).
2. Molecular Quantitative Trait Loci (QTLs), which help identify the specific genes through which genetic variants act.
3. Proteins of the Oxidative Stress Pathway.
This process allowed the team to systematically link MS susceptibility loci to OS pathways.
Pinpointing the Top Targets
By overlapping MS-related gene targets (2,085 unique targets) with proteins from 22 OS-related pathways (931 unique proteins), the researchers identified 85 shared targets.
The reliability of this approach was supported by finding known targets of existing MS drugs, such as KEAP1 (targeted by the antioxidant dimethyl fumarate) and HDAC1 (targeted by the immunomodulator fingolimod).
These 85 targets were then prioritized using a genetic-based score that factored in the strength of association with MS and the presence of QTLs, especially those regulating gene expression in the brain (eQTLs). This prioritization yielded 21 top-scoring targets. Functional analysis confirmed the relevance of these targets, highlighting pathways like "cellular response to stress".
A Brand New Genetic Link: CARM1
Crucially, the study established a potential novel genetic link between MS and the protein CARM1 (Arginine Methyltransferase 1). CARM1 is a transcriptional co-activator known to regulate NF-kB-dependent gene expression and is involved in complex cellular processes like autophagy, differentiation, and cell cycle control.
Selecting the Best Drug Candidates
The team searched public drug databases for modulators of the 21 top targets. To ensure clinical viability, they selected only drugs that were already approved or in clinical trials, and then applied a rigorous in silico prediction of physicochemical properties (ADME-Tox).
The most critical criteria for drug selection included:
1. Central Nervous System (CNS) penetration (ability to cross the Blood-Brain Barrier, BBB).
2. Oral bioavailability.
3. A mechanism of action consistent with the required target modulation (activation or inhibition) derived from the brain eQTLs for the MS risk allele.
This rigorous screening narrowed the field down to 10 repurposable drugs targeting five out of the 21 top targets (MAPK1, STAT3, CDK4, FOS, and CARM1).
Spotlight on Two Key Repurposing Candidates:
The direction of the brain eQTLs for CARM1 and MAPK1 was particularly informative, allowing the selection of two specific drugs with the required modulation:
1. BIIB021 (CARM1 Inhibitor): Genetic analysis suggested that CARM1 expression should be inhibited. BIIB021, an inhibitor of CARM1 (and HSP90), fits this requirement. It is currently in Phase II clinical trials for breast and gastrointestinal tumors and is predicted to easily cross the BBB and be orally administered.
2. PHENETHYL ISOTHIOCYANATE (PEITC) (MAPK1 Activator): MS risk variants were linked to decreased levels of MAPK1 in the brain. Thus, activation was required. PEITC, a bioactive organosulfur compound known to activate the ERK signal (a MAPK1 mechanism) and demonstrate anti-inflammatory and antioxidant activity, was selected. PEITC is currently in trials for lung and oral cancer.
Other selected repurposable drugs include CDK4 inhibitors (ABEMACICLIB, ALVOCIDIB, MILCICLIB, PHA-793887), STAT3 modulators (ERLOTINIB, ENMD1198, ATIPRIMOD), and the FOS inducer PILOCARPINE.
The Future of MS Treatment
This study demonstrates how combining human genetics with OS phenotype data can identify targets that, when dysregulated, contribute to MS pathology. For the first time, it highlights the potential for drugs like BIIB021 and PEITC, which are already in clinical use or trials for other conditions (mainly cancer), to be repositioned as supplements to current disease-modifying MS treatments.
While this in silico work is a powerful step forward, preclinical studies remain essential to validate these candidates in cellular or animal models before their therapeutic application in MS. This novel approach pushes research toward a multitarget drug development strategy, addressing the complex and interrelated biochemical events that drive neurodegeneration in MS.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Olla, S., Steri, M., Formato, A., Whalen, M. B., Corbisiero, S., & Agresti, C. (2021). Combining human genetics of multiple sclerosis with oxidative stress phenotype for drug repositioning. Pharmaceutics, 13(12), 2064.
