Exploring the hidden mechanisms and breakthrough treatments for progressive MS
Multiple sclerosis (MS) has long been characterized by dramatic relapses—sudden attacks of inflammation that damage the nervous system. But for over 1 million people worldwide living with progressive MS, disability accumulates silently and relentlessly, even without relapses.
This form of MS represents neurology's "final frontier": a disease driven by compartmentalized inflammation and neurodegeneration behind a closed blood-brain barrier. Until recently, treatments targeting peripheral immune cells failed to halt this insidious progression. Today, breakthroughs in understanding its pathophysiology are driving a revolution in drug discovery, offering hope where none existed 1 9 .
In relapsing-remitting MS (RRMS), immune cells breach the blood-brain barrier (BBB), causing acute inflammation and demyelination. Progressive MS, however, features a closed BBB, trapping immune cells within the central nervous system (CNS). Microglia (the brain's resident immune cells) and border-associated macrophages become chronically activated, driving a self-sustaining cycle of inflammation and neurodegeneration. This "smoldering fire" persists for decades, leading to cumulative neural damage 9 4 .
Chronic inflammation triggers multiple destructive pathways:
| Feature | RRMS | Progressive MS |
|---|---|---|
| Blood-Brain Barrier | Leaky | Closed/Intact |
| Dominant Inflammation | Peripheral immune cells | CNS-resident microglia/macrophages |
| Primary Driver | Acute flares (relapses) | Slow neurodegeneration |
| MRI Hallmarks | Gd-enhancing lesions | Slowly expanding lesions, atrophy |
| Treatment Target | Adaptive immune cells (T/B cells) | Innate immune cells, neuroprotection |
The Phase III HERCULES trial tested tolebrutinib, an oral Bruton's tyrosine kinase (BTK) inhibitor, in 1,131 patients with non-relapsing secondary progressive MS (nrSPMS). Unlike previous drugs, tolebrutinib crosses the BBB to target microglia and B cells inside the CNS 7 8 .
This trial proved that targeting intracranial immune cells can modify disability progression—a first for nrSPMS. It validated BTK inhibition as a therapeutic strategy and spurred FDA Breakthrough Designation in 2024 8 .
| Reagent/Technology | Function | Breakthrough Application |
|---|---|---|
| Induced Pluripotent Stem Cells (iPSCs) | Differentiate into human oligodendrocytes/neurons | Screening remyelination drugs; modeling patient-specific disease 1 |
| Paramagnetic Rim Lesions (PRLs) | MRI biomarker for chronic active lesions | Predicting disability progression; trial enrichment |
| Neurofilament Light (NfL) | Blood biomarker of axonal damage | Monitoring subclinical neurodegeneration; treatment response 3 |
| BTK Inhibitors | Suppress microglial activation and B-cell function | First disease-modifying drugs for progressive MS (e.g., tolebrutinib) 7 9 |
| Single-Cell RNA Sequencing | Maps gene expression in individual CNS immune cells | Identifying pro-inflammatory microglia subsets 9 |
Dr. Don Mahad's project uses exercise-induced fatigue as an outcome measure to test neuroprotective drugs that enhance neuronal energy metabolism 2 .
BTK inhibitors show promise in early trials for progressive MS
HERCULES trial results published, FDA Breakthrough Designation
Neural stem cell trials expand, combination therapies enter Phase III
Precision medicine approaches based on biomarkers expected
The Progressive MS Alliance mandates patient involvement in trial design, addressing barriers like scientific jargon 6 .
New models classify MS by biology: Cortex-led, Lesion-led, or NAWM-led progression 9 .
Progressive MS is transitioning from a "untreatable" condition to a frontier of innovation. Breakthroughs like BTK inhibitors prove that targeting CNS-resident immune cells can alter disability trajectories. The future lies in precision medicine: pairing biomarkers with therapies that match individual pathobiology. As clinical tools evolve to detect silent progression earlier, and trials embrace patient voices, the once-elusive goal of stopping progression is finally within reach 2 7 .
"The mood is bright at neurology conferences—proof we're turning hope into progress."