How Natalizumab May Help the Brain Heal in Multiple Sclerosis
Multiple sclerosis (MS) is a complex immune-mediated disease where the immune system mistakenly attacks the brain and spinal cord, damaging myelin—the protective sheath around nerves. This leads to inflammation, impaired nerve signaling, and ultimately, disability. Relapsing-remitting MS (RRMS) is the most common form, characterized by cycles of attacks and recovery. While existing drugs can reduce inflammation, understanding their broader effects on the brain’s biology remains a challenge.
A study published in PLOS ONE by Reehorst Lereim et al. (2024) delves into the proteomic changes in the cerebrospinal fluid (CSF) of RRMS patients treated with natalizumab—a potent monoclonal antibody therapy. By using advanced mass spectrometry techniques, the researchers uncovered how natalizumab not only calms immune activity but may also nudge the brain toward repair and regeneration.
What Is Natalizumab?
Natalizumab (brand name Tysabri™) is an anti-inflammatory drug that works by blocking the migration of immune cells into the brain, reducing the damage they cause. It is particularly effective in aggressive cases of RRMS but carries a risk of serious infections like PML (progressive multifocal leukoencephalopathy), which limits its use to specific patient groups.
The Study Design: Tracking Protein Shifts Over Time
The researchers analyzed paired CSF samples from 76 RRMS patients—taken before starting natalizumab and approximately two years into treatment. The study used:
Label-Free LC-MS/MS for broad discovery of proteins.
Parallel Reaction Monitoring (PRM-MS) to confirm findings in a separate cohort.
By focusing on the protein content of CSF—a direct reflection of brain biology—the study offers rare insight into the molecular impact of treatment within the central nervous system.
Key Findings: What Changes After Natalizumab?
Inflammation Cools Down
There was a consistent and significant decrease in immune-related proteins, especially various immunoglobulins (e.g., IgM, IgG subclasses).
Proteins like CHI3L1, CHIT1, and VCAM1, all previously linked to MS activity and inflammation, were also reduced.
These findings reinforce natalizumab’s powerful anti-inflammatory effect.
Repair Signals Rise
Proteins tied to neuronal repair and metabolism went up, such as:
Lactadherin (MFGE8) – involved in neuron development.
Lactate and malate dehydrogenases (LDHA, LDHB, MDH1) – indicating a metabolic shift toward energy renewal.
Glutamate receptor (GRIA4) and LRRC4B – hinting at improved synaptic function.
Not Everything Responds
Some known biomarkers, including vitamin D-binding protein and apolipoproteins A1 and A2, remained unchanged—suggesting persistent disease mechanisms beyond inflammation.
Comparison with Public Datasets: RRMS vs. Treated Brain
Using a large public resource (CSF-PR), the authors compared their results with previous data on RRMS vs. other neurological diseases. The match was revealing:
Many proteins increased in untreated RRMS were reversed by natalizumab, confirming its disease-modifying power.
Conversely, some proteins still changed in the same direction as in active MS, raising the possibility that not all pathological processes are halted.
Why Does This Matter?
This study doesn't just confirm that natalizumab works—it shows how it may enable the brain to enter a healing state. It also hints at the possibility of tailoring treatment monitoring through protein biomarkers, potentially predicting who will benefit most from therapy.
Furthermore, the discovery that certain neurodegeneration-related proteins increase with treatment may open new avenues to explore neuroprotective and regenerative mechanisms—the holy grail in MS therapy.
Final Thoughts: A Step Toward Precision Medicine in MS
The work by Reehorst Lereim and colleagues demonstrates the power of proteomics in uncovering the hidden effects of therapy deep within the brain. While natalizumab remains a double-edged sword due to infection risks, this study shows that when it works, it does more than suppress inflammation—it might help the brain rebuild.
As we move into an era of precision medicine, such detailed molecular maps will be crucial for guiding treatment, monitoring responses, and ultimately, improving quality of life for people living with 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:
Lereim, R. R., Nytrova, P., Guldbrandsen, A., Havrdova, E. K., Myhr, K. M., Barsnes, H., & Berven, F. S. (2024). Natalizumab promotes anti-inflammatory and repair effects in multiple sclerosis. Plos one, 19(3), e0300914.
