Study IDs 4 proteins as potential drug targets for treating NMOSD
2 linked to reduced risk of autoimmune disease, and 2 to higher odds
High levels of two proteins, called FAM3B and PF4V1, are associated with a reduced risk of neuromyelitis optica spectrum disorder (NMOSD), while elevated levels of two other proteins, called CLEC11A and SERPINA1, are linked to increased odds of developing the immune system disease.
These are the findings of a new study by researchers in China, who analyzed potential associations between genetic variants linked to different levels of proteins and NMOSD risk.
The data suggest that these four proteins — three found in the blood and one in the cerebrospinal fluid, or CSF, that surrounds the brain and spinal cord — are “associated with NMOSD and could serve as potential future drug targets,” the researchers wrote.
The results of this genetic analysis were detailed in “Potential drug targets for Neuromyelitis optica spectrum disorders (NMOSD): A Mendelian randomization analysis,” a study published in the journal PLOS One.
The team noted that “clinical trials are required to confirm the findings.”
Researchers cite need for potential drug targets in NMOSD
NMOSD is an autoimmune disease in which the immune system attacks healthy cells in the brain and spinal cord. The disease is usually driven by self-reactive antibodies that target a protein called aquaporin-4 (AQP4).
However, the specific underlying mechanisms of NMOSD remain largely unclear, and “as a result, many existing therapies exhibit limited efficacy, often achieving only partial disease control,” the researchers wrote.
As such, there is a need to identify new potential drug targets, which may help in the development of new and better NMOSD treatments.
Here, a team led by scientists from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology used a technique called Mendelian randomization to identify new potential targets for NMOSD treatment.
This type of analysis uses genetic information to find if a cause and effect exist between an exposure — in this case, levels of a given protein — and an outcome, here, developing NMOSD.
The researchers collected data from a genome-wide association study (GWAS) with 132 people with NMOSD and 1,244 people without the disease. A GWAS is designed to detect associations between genetic variants and a certain trait or disease. The team looked for mutations known to modulate protein levels in people with or without NMOSD.
Higher levels of one protein, FAM3B, linked to 88% reduced risk
If mutations known to be associated with high levels of a particular protein are also found more frequently among people with NMOSD, then it stands to reason that the protein might be involved in the disease, according to the team. Conversely, if such variants are found less frequently in NMOSD patients, then that protein might help prevent the disease from developing.
The analysis identified four proteins — FAM3B, PF4V1, CLEC11A, and SERPINA1 —that seem to be significantly linked with NMOSD risk.
Specifically, data indicated that higher CSF levels of FAM3B were associated with an 88% reduced NMOSD risk, while higher blood levels of PF4V1 were linked with a 53% lower risk.
Conversely, elevated blood levels of CLEC11A were associated with a 13 times higher risk of NMOSD, and higher blood SERPINA1 levels were linked to a twofold higher risk.
The opposing effects of risk or protective proteins suggest [simultaneous] targeting could improve efficacy beyond current immunosuppressive regimens.
Previous studies suggest that FAM3B and PF4V1, also known as CXCL4L1, have anti-inflammatory effects. Also, CLEC11A has been suggested to be involved in chronic neurodegenerative processes, and SERPINA1 has anti-inflammatory and pro-inflammatory functions.
The team conducted a reverse Mendelian randomization to explore the influences of NMOSD on the levels of these proteins, and it “showed no evidence of NMOSD-driven protein changes,” the researchers wrote.
This further suggested that changes in the levels of these proteins are likely involved in the development of, or protection against, NMOSD, and are not a consequence of the disease.
“Although these are preliminary findings, the results suggest that both [blood] and CSF may be effective for detecting NMOSD-related proteins,” the scientists said. “The opposing effects of risk or protective proteins suggest [simultaneous] targeting could improve efficacy beyond current immunosuppressive regimens.”
The team noted as a study limitation that their work was based on data from people with European heritage. Thus, the findings may not be generalized to other ethnicities. Additionally, the team wrote, “further investigation should explore the potential mechanisms related to these proteins in NMOSD.”
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