Targeting Neuroinflammation in Multiple Sclerosis

Timothy J. Turner, Global Program Head for Neurology at Sanofi

How MS affects the brain

In MS, the immune system attacks healthy tissue and causes damage to the brain and spinal cord for reasons we don’t understand. The defining feature of this autoimmune attack is the damage it wreaks on the myelin sheath inside the CNS. This protective covering surrounds the long, cable-like axons that conduct electrical signals between neurons, which carry information between the brain and other parts of the body in a massive network. 

Neuroinflammation breaks the myelin sheath apart in a process called demyelination, and this can ultimately damage the axon, cutting the connection between neurons. These degenerative processes can start early in MS, before a patient—or someone in their life—spots any signs of the disease, such as lack of coordination or difficulty walking.

How neuroinflammation starts

There are always immune cells working inside the brain: resident immune cells carrying out routine maintenance, and immune cells from the periphery that cross the blood-brain barrier to carry out “immune surveillance”. In MS, both types can become aggressive and malfunction:

• T-cells, antibody-producing B-cells, and other immune cells that cross the blood–brain barrier can attack the brain and spinal cord. 
• Within the CNS and outside of it, B-cells release substances called cytokines that trigger inflammation.

Chronic lesions

The resulting damage in the brain can be detected using advanced MRI techniques: they appear as lesions, with immune cells and myelin debris clustered along the edges. At that point, one of three things can happen to the axons: 

• they could become re-myelinated; 
• they could become inactive without being remyelinated; or 
• they might continue to degenerate. 

Some lesions represent sites of chronic, 'smoldering' inflammation in the brain. These smoldering lesions have been associated with brain volume loss, disability, and disease progression.

Compounding the damage

When cells in the CNS are destroyed, the resulting debris attracts the attention of innate immune cells like microglia, which normally have a "clean up" role inside the CNS. Unfortunately, this can cause further damage.

Microglia reside in the brain and spinal cord, and actively maintain the health of the CNS. Among many beneficial functions, they patrol for signs of cellular damage or pathogens that trigger an innate response. In MS, what starts out as a protective function becomes a destructive one: the debris from demyelination causes microglia to go into overdrive and destroy normal tissue. This neuroinflammatory process may contribute to further myelin destruction. It creates a hostile environment and prevents repair processes that would normally foster re-myelination. 

To limit or repair the damage, it is crucial that we find ways to control it. Because microglia reside in the CNS, any potential treatment would need to cross the blood–brain barrier to affect them.

Crossing the blood–brain barrier

The blood–brain barrier keeps tight control over everything that enters or leaves the CNS. It's one reason most MS treatments, for example antibody therapies, are designed to target cells outside the CNS: blocking unwanted T-cells and B-cells from entering the brain can actually limit some degenerative activity inside the brain.

Developing a treatment that could cross the blood–brain barrier, get into the CNS and act directly on immune cells is an important frontier in research at Sanofi. As we understand more about MS, we can focus on specific targets within the brain that haven't been accessible before.

Targeting BTK

For any drug to enter the CNS, it must evade the body's sentinel system, which blocks unwanted substances from entering the brain. Sanofi scientists are investigating ways to target an enzyme called Bruton's tyrosine kinase (BTK).

BTK is critical to the activation of many immune cells that drive MS, such as B cells and microglia, and has gained attention for the role it plays in immune activities on both sides of the blood–brain barrier. That's why we believe that a treatment that could inhibit BTK within the brain may be able to calm the activity of microglia and other immune cells, shifting them back into a more normal state.

Looking ahead

The scientific community has known that MS is a demyelinating disease of the brain since the 1870s, but only recently has it become possible to target over-active immune cells in the brain. New approaches to chemistry and novel methods to "shuttle" proteins across the blood–brain barrier have reset expectations for what is possible in neurology research. Our teams are leveraging these new technologies to pursue a new generation of therapies that would have been unattainable just a decade ago. And that is a really exciting place to be.

By Timothy J. Turner, Global Program Head for Neurology at Sanofi