6 cellular markers that could lead to novel or repurposed treatments
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Scientists have pinpointed six cellular targets that could open new doors for developing or repurposing treatments to stop progressive MS. (Photo from iStock)
Scientists have identified six proteins that could serve as targets for new treatments designed to slow multiple sclerosis (MS) progression.
The data showed that one protein, RRM2B, may interact with the approved MS treatment Mavenclad (cladribine), while the other proteins interacted with molecules that are not currently used in MS care but could potentially be repurposed, according to a new study.
“We identified six key proteins that may provide new biological insight into progressive multiple sclerosis and support future therapeutic exploration,” Yuang Jiang, PhD, the study’s first author from Karolinska Institutet in Sweden, said in a university news story.
Findings were detailed in a study, “Multi-omics integration provides biological insight and prioritizes potential drug targets in multiple sclerosis progression,” published in the Journal of Neuroinflammation.
Several disease-modifying therapies are available for MS, a neurodegenerative disease in which the immune system erroneously launches inflammatory attacks against healthy parts of the brain and spinal cord.
However, most of these treatments target the inflammation that plays a predominant role in earlier stages of MS that are characterized by relapses, but have limited efficacy against the chronic neurodegenerative processes that drive disability accumulation in the long-term.
“These limitations stress an urgent need for continued efforts in drug discovery, development, and repurposing to better address MS development,” the researchers wrote.
The goal of the research was to identify new therapeutic targets with promise for addressing MS progression.
First, the team examined data from a large genome-wide association study that analyzed genetic data from thousands of MS patients to identify genetic variants associated with MS progression.
They looked at how those findings overlapped with data from protein quantitative trait loci studies, which show how genetic changes affect protein levels in the blood and brain.
Through a series of analyses, the researchers gradually narrowed down a list of dozens of proteins that could be involved in MS progression.
They considered various factors, including whether the proteins were involved in MS-relevant biological pathways, if they were present in disease-associated cell types, and if they interacted with targets of existing MS medications.
Other analyses showed whether there were drug repurposing opportunities, meaning whether some of the proteins might interact with medications used for other conditions that could also hold therapeutic promise for MS progression.
Ultimately, the scientists came up with a short list of proteins that could be therapeutic targets for MS progression: RRM2B, CBR1, ETFA, DNM3, CAB39L, and NMRAL1.
Of particular interest was RRM2B, a protein involved in DNA repair that showed potential interactions with Mavenclad and a related molecule called clofarabine, which is used to treat certain cancers.
While Mavenclad is known to effectively suppress MS relapses, the data suggest it may also act on the neurodegenerative processes that drive disability progression.
“Our identification … provides a genetically supported rationale to re-evaluate cladribine in robustly designed trials focused on neurodegeneration,” the researchers wrote, noting that clofarabine, not currently used for MS, could also be explored as a new option.
The other identified targets influenced various processes relevant to MS. For example, CBR1 helps dampen oxidative stress, a type of cellular damage thought to contribute to MS, while DNM3 influences nerve cell signaling, and NMRAL1 affects immune function. Some of these have been studied in the context of MS, and others have not.
“Our findings contribute to the understanding of the complex nature of MS progression by identifying key proteins involved in multiple pathological [disease-related] processes,” the researchers wrote.
Some proteins interacted with numerous molecules that could be repurposed to target MS progression. Among them were certain flavonoids, a group of plant compounds that give fruits and veggies their color.
“Collectively, these findings suggest several potential therapeutic strategies for MS progression, providing a rationale to re-evaluate existing drugs for novel adjunctive MS treatments,” the scientists wrote.
They noted, however, that the data are preliminary and do not confirm the efficacy, safety, or clinical relevance of the therapeutic targets they identified.
“Rigorous functional studies are required to validate the biological roles of the prioritized proteins, confirm their therapeutic relevance in disease models, and evaluate whether modulation of these targets could have clinical utility in MS progression,” the researchers noted.
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