Podcast Summary: MS Living Well

Episode: Repairing MS – The Quest to Rebuild Myelin

Date: September 9, 2025
Host: Dr. Barry Singer, MD
Guests: Prof. Veronique Marron (University of Toronto), Dr. Robert Glanzman (Find Therapeutics)

Overview

This episode dives deep into the science and future of repairing myelin—the protective covering around nerves—damaged in multiple sclerosis (MS). Dr. Barry Singer speaks with leading experts Professor Veronique Marron and Dr. Robert Glanzman about advances in remyelination research, challenges in drug development, and hope for people with MS. The conversation covers how myelin works, why it fails to repair, what’s being tried in clinical trials, and the realistic timelines and hurdles for myelin repair therapies.

Key Discussion Points & Insights

1. What Is Myelin and Why Does It Matter?

[02:03–03:19]

• Myelin is the insulating layer around nerves in the central nervous system (CNS), made by oligodendrocytes.
• Provides two critical functions:
  • Insulation for electrical signals, ensuring rapid and reliable nerve communication.
  • Trophic support: Supplies survival and energy factors to keep nerve fibers healthy.
• Without myelin, electrical signals are disrupted and nerves are vulnerable to degeneration, a key driver of progression in MS.
  Prof. Marron: "It's not just insulation... it really provides factors that support the energy demands of the nerve." [02:59]

2. Mechanisms of Demyelination and Remyelination

[03:53–07:20]

• Demyelination is primarily driven by misdirected immune attacks, causing loss of myelin and nerve dysfunction.
• Symptoms (like vision problems or numbness) arise from failed signal transmission and insufficient support to nerves.
• Remyelination (natural repair of myelin) does happen, especially in younger patients or early in MS—but it’s often incomplete and slows with age and disease progression.
• Recovery after attacks is slow (weeks to months) because building new myelin is an energy-intensive, multi-step process.

3. The Role of Oligodendrocyte Precursor Cells (OPCs)

[09:30–10:40]

• OPCs are “stem-like” immature cells—5–8% of CNS cells—capable of becoming myelin-making oligodendrocytes.
• Everyone has OPCs, but their efficiency declines with age and MS progression.
• Factors in the MS lesion environment, especially molecules from immune cells, often block OPC maturation or recruitment into damage sites.

4. Roadblocks to Full Remyelination

[11:18–13:10]

• Major obstacles:
  • Age-related decline in OPC number/function.
  • Blocked maturation of OPCs due to changes in the brain environment.
  • Inability of new oligodendrocytes to efficiently make myelin—especially influenced by blood-derived monocytes and local immune responses.
• Prof. Marron’s research: Identified that monocytes entering lesions reduce the remyelination ability of newly formed oligodendrocytes.

5. Microglia: Double-Edged Sword

[13:37–16:16]

• Microglia are brain-resident immune cells; their role changes depending on their “state.”
  • Helpful: Clearing myelin debris (“taking out the garbage”) and secreting factors (e.g., Activin A) that promote OPC maturation.
    • "One way in which microglia can help remyelination is by clearing out that debris… If that debris is not cleared up, it actually blocks the OPCs from coming into the lesion." – Prof. Marron [13:37]
  • Harmful: In chronic active lesions, become inflammatory, block repair, and cause further damage.

6. BTK Inhibitors: A Promising Drug Class

[16:16–18:48]

• BTK inhibitors (new drugs under development) target the BTK protein, which is abundant in microglia and B cells.
• The idea: Reduce harmful inflammation from microglia and potentially help them support remyelination.
• Current clinical trials are exploring if BTK inhibitors can shift microglia from damaging to helpful states, especially in progressive MS.

7. Recruiting & Maturing OPCs: The Challenge

[18:48–20:34]

• Lesions often lack the right “attractant” factors to pull OPCs in, or contain “repellant” signals.
• Accumulated myelin debris creates an environment that blocks both OPC entry and their maturation.

8. Outlook for Remyelination

[20:50–21:40]

• Biggest needs:
  • Drugs that can stimulate remyelination in older individuals.
  • Reliable “readouts” (biomarkers) showing successful myelin repair in clinical settings.
• Prof. Marron: “I think the clinical trials are really encouraging, and this field is pushing at a very quick speed, and I think we're going to get there.” [21:32]

New Drug Strategies and Clinical Trials

9. Why Past Human Clinical Trials Failed

[24:11–25:56]

• Early drugs (antibodies like alizanumab and opacinumab) worked in animal models but didn't translate to benefit in people.
• Key issues: Large antibody drugs have trouble penetrating the blood-brain barrier—less than 1% actually reach targets in the brain.
• Dr. Glanzman: “For most companies, only about 0.5% of the injected dose gets to the brain. So 99.5% of your drug is...not reaching the target.” [25:16]

10. New Targets – Repulsive Guidance Molecules and the Semaphorin Pathway

[26:36–28:13]

• In MS, molecules like semaphorin 3A (a guidance molecule usually active in embryonic development) are mistakenly reactivated and block OPCs from entering lesions and maturing.
• FTX101 (a peptide targeting this pathway) is in development to break this inhibitory cycle and enable remyelination.

11. Drug Repurposing: Clemastine and Metformin

[28:13–32:05]

• Clemastine (an old antihistamine drug) was shown by Dr. Ari Green (UCSF) to slightly improve myelin repair in the optic nerve.
  • Visual Evoked Potentials were used to prove improved myelin conduction, with some visual function benefit as well. [28:46–31:01]
• Metformin (a diabetes drug) also shows some promise, but has controversial side effects (e.g., hypoglycemia, diarrhea) in people without diabetes.
• Both are now in further clinical trials, with more potent and selective successors (e.g., PIPE-307, a specific M1 muscarinic receptor antagonist).

12. Gold Nanoparticles – An Unorthodox Approach

[32:19–34:34]

• Gold nanoparticles (oral solution): Early trial (Visionary MS) showed possible benefit.
• Theory: Help cells in the CNS make more energy, but the exact mechanism remains unclear.
• Dr. Glanzman: “[Gold nanoparticles] allow those cells to make energy. That's really what's going on.” [34:29]

13. Imaging and Proving Myelin Repair

[35:44–36:32]

• MRI methods (e.g., diffusion tensor imaging, magnetization transfer ratio) and visual evoked potentials are tools to measure remyelination in research.
• Regulatory challenge: FDA demands proof of clinical benefit—not just evidence of remyelination by imaging or electrophysiology.

Memorable Quotes & Standout Moments

• Dr. Singer: “Kind of think of it like an octopus… all these arms reaching out, tentacles and just wrapping around. And that takes time for that to happen.” [08:45]
• Prof. Marron: “Microglia can have different states… In the same way, we as people can be in a happy state or an angry state.” [15:15]
• Dr. Glanzman: “5 to 10% of the cells in your brain and spinal cord are these immature cells that could become remyelinating cells. So it's not like the cells aren't there. But one of the problems is, they don't really get into the lesions very well.” [26:36]
• Dr. Glanzman on patient urgency: “My patients are on me. That's a tough crowd, buddy.” [32:42]
• Dr. Glanzman on realistic timelines: “For my compound... phase three can't really start until 2029, maybe 2030, and then you're looking at three to five years... 2033, we may have a remyelinating drug on the market." [37:06]

Timelines, Challenges, and Hope

14. Drug Development Timelines

[37:06]

• Current compounds are in early to mid-stage clinical trials.
• Best realistic estimate for a remyelinating drug on the market: 2033.
  • “Unfortunately, it's a long and tedious process…” – Dr. Glanzman

15. Advocacy and Next Steps

[36:41–36:55]

• Further progress needs government and private investment in both basic and clinical research.
• Call to action: Engage with policymakers to support funding for MS research.

Useful Timestamps

| Topic | Timestamp | |-----------------------------------------------|------------| | What is myelin? | 02:03 | | Demyelination explained | 05:58 | | Natural remyelination/recovery | 07:20 | | OPCs and their importance | 09:44 | | Microglia’s dual role | 13:37 | | BTK inhibitors in MS | 16:16 | | Obstacles in OPC recruitment | 18:48 | | Learning from failed antibody drugs | 24:30 | | Clemastine & visual evoke potential studies | 28:46 | | Gold nanoparticles | 32:51 | | Imaging/myelin detection in research | 35:44 | | Timeline to first remyelination drug | 37:06 |

Conclusion & Takeaway

• Remyelination is possible, and the central nervous system already has the fundamental machinery (OPCs and oligodendrocytes) for repair.
• The main challenge: overcoming the hostile lesion environment in MS, boosting OPC recruitment/maturation, and finding drugs that work for older, progressive MS patients.
• Several promising strategies are advancing—targeting guidance molecules, repurposing old drugs, BTK inhibitors, and even gold nanoparticles—but no cure is imminent.
• The first remyelinating treatment, even in the most optimistic scenario, is still nearly a decade away.
• Patients and providers can support the process by advocating for greater investment in research and participating in clinical trials.

“The road is long but the progress is real... the hope of restoring function for people living with MS has never been closer.” – Dr. Barry Singer [37:55]

For more details, visit the episode notes at mslivingwell.org.