Researchers at the Karolinska Institute in Sweden said they have identified 18 new potential protein drug targets to treat multiple sclerosis (MS) using an integrative analytical approach.
A drug target is a molecule, typically a protein, within the body that’s often involved in disease processes. Some of the newly discovered proteins are targeted by existing non-MS drugs, suggesting these therapies may be repurposed to treat MS.
The discovery was reported in the study, “Multiomics integration prioritizes potential drug targets for multiple sclerosis,” published in the Proceedings of the National Academy of Sciences.
“Our results demonstrate significant potential for both the discovery of new drugs and the repurposing of existing ones,” Yuan Jiang, a PhD candidate at the Karolinska Institute and the study’s first author, said in a university news story.
MS is marked by inflammatory damage to healthy parts of the brain and spinal cord. While several disease-modifying therapies (DMTs) are available to manage the disease by reducing the frequency and severity of relapses and delaying disability progression, more effective therapies are needed, especially for people with progressive forms of MS.
Identifying proteins, looking for roles in MS
“Continuous exploration of drug discovery, development, and repurposing has become increasingly crucial for improving both the efficacy and the safety of MS treatment,” the researchers wrote.
To identify candidate proteins linked to MS, the Karolinska researchers first conducted a proteome-wide association study (PWAS), a method that looks for relationships between protein levels in the blood and brain and MS susceptibility. Here, 100 proteins in the blood and 212 proteins in brain tissue had levels that were significantly associated with MS susceptibility.
A technique called summary-data-based Mendelian randomization was then used to determine whether any of the proteins identified by PWAS played a causal role in MS. Overall, nine blood and nine brain proteins were considered causal and thus potential drug targets.
Among the blood proteins, CR1 and WARS were associated with an increased risk of MS, whereas TNFRSF1A, FCRL3, TYMP, PGLYRP1, CD59, IDUA, and ARHGAP1 were linked with a reduced risk of MS. In the brain, HLA-B, ZC2HC1A, HMGCL, TSFM, FAM120B, TRAF3, and MTHFR were tied to an increased risk of MS, while ICA1L and AUH were associated with a decreased MS risk.
Further experiments revealed that blood proteins were mostly produced by immune cells involved in MS, while brain proteins were mostly sourced to nerve cells and other supportive brain cells such as oligodendrocytes, the cells that produces myelin in the brain and spinal cord, astrocytes, and blood vessel cells.
A subsequent analysis found that five of the nine blood drug targets interacted with 19 known targets of 10 approved MS medications. Likewise, two of the nine brain drug targets interacted with five known drug targets of six MS therapies.
Four of the blood-based targets and two brain-based targets were also targeted by 16 existing drugs not used in MS, “suggesting potential opportunities for drug repurposing,” the team wrote.
“By integrating large-scale … data and applying advanced statistical methods, we have been able to prioritize drug targets that may improve the treatment of MS,” Jiang said.