How Natalizumab May Help Repair the Brain in Multiple Sclerosis

In the complex world of multiple sclerosis (MS) treatment, a new study from researchers across Norway and the Czech Republic offers a hopeful twist: the popular MS drug natalizumab may not just calm the immune system—it might also kickstart repair in the brain and spinal cord.

This comprehensive proteomics study, published in PLOS ONE in March 2024, dives deep into the protein makeup of cerebrospinal fluid (CSF) from MS patients before and after two years of natalizumab therapy. The team, led by Ragnhild Reehorst Lereim and colleagues, used state-of-the-art mass spectrometry to ask a simple but powerful question:

What happens inside the brain’s molecular soup when MS patients are treated with natalizumab long-term?

The Basics: What’s MS and Why Use Natalizumab?
Multiple sclerosis is a neurological disease where the body’s immune system attacks the protective myelin sheath around nerves. The most common form, relapsing-remitting MS (RRMS), involves unpredictable flare-ups of neurological symptoms.

Natalizumab, a monoclonal antibody, helps by blocking immune cells from crossing into the brain—essentially putting up a “No Entry” sign at the blood-brain barrier. It’s known for reducing relapses and MRI-visible lesions, but this study reveals it might be doing something more.

The Study Design: 76 Patients, 2 Years, and a Lot of Proteins
The researchers analyzed CSF samples from 76 RRMS patients—before starting natalizumab and after about two years of therapy. First, they used label-free liquid chromatography–mass spectrometry (LC-MS) to identify protein changes. Then, they double-checked key findings with a more targeted technique (PRM) in a new group of 20 patients.

They identified 287 proteins whose levels shifted significantly with treatment.

What Changed in the Brain’s Protein Profile?
1. Inflammation-Linked Proteins Decreased
Some of the biggest drops came from:

Immunoglobulins (IgM, IgA, IgG) – markers of adaptive immune response.

CHI3L1 and CHIT1 – chitinase-related proteins linked to disease progression.

VCAM1 – a molecule that helps white blood cells sneak into the brain.

CD163 – a marker of macrophage activity.

These findings back up what clinicians already see: natalizumab is a powerful anti-inflammatory.

2. Neuronal and Metabolic Proteins Increased
More intriguingly, several proteins associated with brain function and energy metabolism were increased:

Lactadherin (MFGE8) – involved in neuron development and repair.

Lactate and malate dehydrogenases (LDHA, LDHB, MDH1) – key to mitochondrial energy processes.

Amyloid precursor protein (APP) – linked to synaptic plasticity and neurorepair.

In essence, the protein changes suggest that natalizumab may open the door to restorative processes, not just immune suppression.

Repair, or Just Less Damage?
Here’s the twist: some of the proteins that increased after treatment were decreased in untreated RRMS patients according to public databases. That suggests these changes might represent a partial reversal of disease-related damage.

Still, not all markers moved. For instance:

Vitamin D-binding protein (GC) and apolipoproteins A1 and A2 (APOA1, APOA2) remained unchanged, hinting at underlying disease mechanisms untouched by natalizumab.

This observation is critical—it underscores that while natalizumab quiets inflammation, it may not halt all aspects of MS progression.

Biomarker Validation: The Gold Standard
The authors didn’t stop at discovery. They verified 54 of the most affected proteins using targeted PRM mass spectrometry in a new cohort. Impressively, many findings held up, especially:

IGJ and IGHM (key immunoglobulin chains)

VCAM1

MFGE8

APOL1

This validation gives their results serious scientific weight.

Why It Matters
This study does more than catalog protein shifts—it points toward potential biomarkers to monitor treatment and possible new therapeutic targets. The identification of increased proteins linked to neuroregeneration may help explain why some patients improve functionally on natalizumab.

Even more, it hints at personalized MS care in the future. If certain protein profiles predict who benefits most from natalizumab—or who still needs more intervention—we could move closer to truly tailored therapies.

Final Thoughts
This paper provides a detailed molecular snapshot of how natalizumab reshapes the MS disease environment in the central nervous system. While it doesn’t claim that the drug regenerates brain tissue, it offers a tantalizing glimpse that some repair-oriented pathways might be activated during treatment.

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 RR, Nytrova P, Guldbrandsen A, et al. Natalizumab promotes anti-inflammatory and repair effects in multiple sclerosis. PLOS ONE. 2024 Mar 25;19(3):e0300914. https://doi.org/10.1371/journal.pone.0300914