CMT Simplified

CMT Biomarkers Can't Wait

• Hereditary Neuropathy Foundation • Season 1 • Episode 11

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A slow-burning disease like Charcot Marie Tooth can fool even the best trials. Scores swing with sleep and stress, not biology, while tiny changes accumulate out of sight. We set out to replace guesswork with measurement and show how the right biomarkers can compress timelines, cut costs, and turn promising science into treatments that matter.

First, we unpack the measurement problem and why functional scales are too noisy for a disease that changes over years. Then we get concrete. MRI fat fraction reveals muscle-to-fat replacement in just 43 days, letting us see whether a therapy slows degeneration without waiting 18 months for a clinic score to budge. From there we move molecular: proteomics shows drops in extracellular matrix and neuronal development proteins alongside rising metabolic stress signals, reframing CMT as both a structural and metabolic disorder. That shift sets up a powerful case study—sorbitol accumulation traced to an enzyme defect—where a biomarker connected patients to a drug already in development for another condition.

We also highlight the rise of digital biomarkers that live where patients do. Wearables capture fatigue, drop foot, and real stair performance over weeks, producing real-world evidence that complements imaging and blood markers. None of this works without patient partnership, so we talk candidly about biobanks, why longitudinal samples are non-negotiable, and how skin cells reprogrammed into neurons enable personalized drug screens without invasive nerve biopsies. Finally, we tackle the big strategic question: will a universal marker like neurofilament light unlock progress across 100-plus genetic subtypes, or do we need a unique fingerprint for each?

If you care about faster trials, smarter endpoints, and bringing CMT treatments to the pharmacy shelf sooner, this deep dive is for you. Subscribe, share with someone in the CMT community, and leave a review with your take: master biomarker or many subtype markers?

Ways to take action now

1) Donate blood at an HNF Roadshow:
You can donate blood for biomarker research at an HNF Roadshow near you. Click on the “Location” tab to view 2026 dates and sites:

2) Join Studies & Donate blood at the CMT Summit + Retreat:
Attending the Summit? You can also donate blood on-site to support HNF’s biobank and biomarker discovery efforts—helping accelerate progress toward FDA-qualified measures and future treatments.

3) Join or update GRIN:
If you’re already in the GRIN Registry, please log in and complete any annual updates—every data point strengthens the research.

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SPEAKER_00:

I want you to picture the most frustrating puzzle in the world. You're trying to put it together, but um the pieces are changing shape.

SPEAKER_01:

Right.

SPEAKER_00:

And the worst part, they're changing so slowly that if you stare right at them, they'll look exactly the same. You can't see it happening. But if you walk away and come back a year later, the picture is, well, completely different.

SPEAKER_01:

Aaron Powell That is a terrifyingly accurate analogy. I mean, unfortunately, that is the daily reality for researchers trying to cure these slow progressing diseases. It's the whole paradox of the slow burn.

SPEAKER_00:

Aaron Powell And it leads to this really kind of ethical nightmare of a question, doesn't it? What happens when a clinical trial fails? Not because the drug was bad, but simply because researchers couldn't actually see the changes happening fast enough to prove it worked.

SPEAKER_01:

Aaron Powell That right there is the billion-dollar culture. It's the bottleneck of uh modern neurology. And today we are doing a deep dive into charcomerie tooth disease or CMT. And we're looking at why the hunt for something called biomarkers isn't just some abstract science project. It is literally an emergency race against time.

SPEAKER_00:

Aaron Powell And to guide us, we are digging into a fascinating set of materials from the Hereditary Neuropathy Foundation or HNF. Specifically, we're unpacking the transcript from their webinar, Why Biomarkers Can't Wait. We've got insights from the HF founder, Allison Moore, and some uh some real heavy hitters in the research world, Dr. Matt Jarp, Dr. Ricardo Ramirez, and Dr. Rita Horvath.

SPEAKER_01:

It's a powerhouse lineup. And the mission for this deep dive is, you know, pretty clear. We need to understand how we bridge that gap. How do we move from subjective feelings like I feel a bit weaker today, to objective hard data.

SPEAKER_00:

Aaron Ross Powell Because the consensus seems to be that without that shift, we are just stuck.

SPEAKER_01:

Completely stuck in the mud.

SPEAKER_00:

So let's unpack the core problem first. Allison Moore kicked this off with a phrase that honestly it applies to everything, not just medicine. You can't fix what you can't measure.

SPEAKER_01:

It's the measurement problem. And to understand why this is such a crisis in CMT, you have to look at how we've um traditionally run clinical trials. Historically, they rely on what are called functional scales.

SPEAKER_00:

Aaron Powell These are the checklists, right? I've seen these. A doctor sits you down and asks, how well can you button your shirt? Or, you know, can you pick up this little peg?

SPEAKER_01:

Aaron Powell Exactly. Or the classic pain scale. Rate your pain from zero to ten.

SPEAKER_00:

Which on the surface seems logical. I mean, if I can't button my shoot today and I take a drug and next year I can, the drug worked. Why isn't that good enough?

SPEAKER_01:

In theory, it absolutely should be. But in practice, and Dr. Matt Jarp was really emphatic about this, that data is incredibly noisy.

SPEAKER_00:

Noisy is a very polite way of saying messy, isn't it?

SPEAKER_01:

It is. Yeah. Let's take that pain scale. You might walk into the clinic on a Tuesday and say your pain is a four.

SPEAKER_00:

Okay.

SPEAKER_01:

But on Wednesday, maybe you slept funny. Maybe you're stressed about work.

SPEAKER_00:

Or, as Dr. Jarpy mentioned, maybe you have screaming kids running around the house and your head is splitting, so everything just feels worse.

SPEAKER_01:

Precisely. And suddenly that four becomes an eight. Did your CMT progress overnight? Did your nerves die back in 24 hours? Of course not. Life happened. But if you put that eight into a spreadsheet for a clinical trial, it looks like a massive spike in disease activity.

SPEAKER_00:

Right. That's bad data.

SPEAKER_01:

That is bad data. It fluctuates way too much to be a reliable ruler.

SPEAKER_00:

And then you add the nature of CMT itself on top of all that. I mean, this isn't a fast-moving infection like the flu. It's a slow erosion.

SPEAKER_01:

Right. This is the natural course challenge. If you give a patient a drug and they don't get worse for a year, is it the drug? Or is it just that the disease is moving that slowly anyway?

SPEAKER_00:

Because you just can't see the microscopic changes.

SPEAKER_01:

You're flying blind. And because you're flying blind, you have to run the trial for two, three, maybe four years to see a difference with those button-the-shirt tests.

SPEAKER_00:

Which costs millions and millions and millions.

SPEAKER_01:

And often at the end of it all, the noise in the data, the screaming kids, the bad sleep, it washes out the results, the trial fails, and we're right back to square one.

SPEAKER_00:

So the reeler is broken. The solution is this buzzword that's in the title of the webinar. Biomarkers. Now I feel like we hear this word thrown around all the time, but let's actually define it. What is a biomarker in this context?

SPEAKER_01:

In the simplest terms, a biomarker is a measurable sign something biological that agencies like the FDA can trust. It's objective. It doesn't care if your kids are screaming, it just tells you what the biology is doing.

SPEAKER_00:

Aaron Powell So moving from do you feel hot to actually using a thermometer?

SPEAKER_01:

Aaron Powell That is the perfect analogy. A thermometer is a biomarker for fever. For CMT, we are looking for that thermometer. And the goal is um really twofold. First, it lets researchers do something called enrichment.

SPEAKER_00:

Enrichment. That sounds like we're talking about uranium or something. What does that mean for a trial?

SPEAKER_01:

Aaron Powell It means stacking the deck in your favor. If you have a biomarker, say a blood test, that tells you a specific patient is on the verge of a rapid decline, you put them in the trial.

SPEAKER_00:

Aaron Powell Ah, so you pick the people who are most likely to show a response.

SPEAKER_01:

Aaron Powell Exactly. You reduce the noise. But there was another goal mention that felt a bit uh counterintuitive at first, the idea of failing fast.

SPEAKER_00:

Aaron Powell Yeah, I flag that too. I mean, usually failure is what we're trying to avoid. Why do we want to fail?

SPEAKER_01:

Aaron Powell Because resources are finite. Money, time, patient patience, all of it. If a drug doesn't work, we want to know in three months, not three years. Okay, I see. We want the trial to fail quickly and definitively so we can stop spending money on a dead end and pivot to a drug that might work.

SPEAKER_00:

Efficiency through failure. It's a tough pill to swallow, but it makes total sense. You don't want to chase a ghost for a decade.

SPEAKER_01:

It's essential. And Dr. Jarrtpin showed this incredible example of how biomarkers can speed this up involving MRIs. He talked about something called the fat fraction.

SPEAKER_00:

This blew my mind. I've seen MRIs, but I never thought about them as like a quantitative tool like this. Break down the fat fraction for us.

SPEAKER_01:

Aaron Powell So on a standard MRI, healthy muscle tissue looks black. Fat tissue looks white. In CMT, the main issue is that nerves die back. When the nerve disconnects from the muscle, the muscle atrophies, it shrinks, and the body replaces that empty space with fat.

SPEAKER_00:

Aaron Powell So the leg muscle literally turns from black to white on the scan over time.

SPEAKER_01:

Now, here is the nugget that matters. Dr. Darpey shared a study where they used MRI to track this specific change. They detected a significant measurable change in muscle mass in just 43 days.

SPEAKER_00:

Aaron Ross Powell 43 days? That's barely a month and a half.

SPEAKER_01:

Compare that to the clinical scales.

SPEAKER_00:

Right. If you relied on the shirt test or the patient saying, my leg feels a bit weaker, it might have taken what 18 months to notice that.

SPEAKER_01:

Maybe longer. But the MRI, the biomarker, saw the biology changing in real time. That is the acceleration we're talking about. Wow. If a drug stops that change, you know, in 43 days, not two years.

SPEAKER_00:

Aaron Powell So that's imaging. That's seeing the disease from the outside in. But the webinar also went deeper, literally into the molecular level. They started talking about proteomics. This is where Dr. Ricardo Ramirez came in.

SPEAKER_01:

Right. Dr. Ramirez was digging into data from the combined brain database. He was taking blood plasma from CMT patients and comparing it to people without CMT. And he wasn't looking for one thing. He was looking at thousands of proteins at once to see what was acting weird.

SPEAKER_00:

It's like a dragnet. You're just seeing who looks suspicious.

SPEAKER_01:

Exactly. And he found some really specific patterns. He found that certain proteins were way lower in CMT patients. Specifically, proteins involved in extracellular matrix organization.

SPEAKER_00:

Okay, hold on. Extracellular matrix organization. That is a mouthful. Explain that like I'm five.

SPEAKER_01:

Think of your body like a brick wall. The cells are the bricks. The extracellular matrix or ECM is the mortar. It's the glue, the scaffolding that holds the structural integrity of your tissues together. Aaron Powell So Dr.

SPEAKER_00:

Romeris has seen that the glue proteins are just missing.

SPEAKER_01:

Significantly lower. Which makes sense. If structural integrity is failing, the nerves and muscles can't maintain their connection.

SPEAKER_00:

A structural collapse.

SPEAKER_01:

It suggests a structural collapse. He also found a drop in proteins related to neuronal sculpting.

SPEAKER_00:

Which sounds very artistic.

SPEAKER_01:

It's actually developmental. These are the genetic programs that tell a neuron how to shape itself, how to extend its branches, its axons, to make the right connections.

SPEAKER_00:

And those were down.

SPEAKER_01:

Those were downregulated. So you have the glue failing, and you have the blueprint for the neurons failing. Trevor Burrus, Jr.

SPEAKER_00:

That's a double whammy. But I remember there was also stuff that went up, things that were skyrocketing.

SPEAKER_01:

Aaron Powell Yes. And this is where it arguably shifts our entire understanding of the disease. The proteins that were shooting up were all associated with disease of metabolism.

SPEAKER_00:

Metabolism. I always just think of that as, you know, how fast I burn calories.

SPEAKER_01:

Aaron Powell Well, in a cellular sense, it's how your body processes energy, lipids, fuel. Seeing these marker spikes suggests that CMT isn't just a structural problem where nerves disconnect. It implies the body's entire metabolic engine is going haywire.

SPEAKER_00:

Aaron Powell Which is a massive clue if you're designing a drug. You're not just trying to fix the wire. You might need to fix the power plant.

SPEAKER_01:

Exactly. It broadens the target list. And that metabolic clue is the perfect segue to what I think was the biggest aha moment of this entire deep dive: the story of the S or D gene.

SPEAKER_00:

Aaron Powell This story is honestly the best argument for why this research matters. It's not abstract at all.

SPEAKER_01:

It is the validation.

SPEAKER_00:

So set the scene for us. What was the situation for these patients?

SPEAKER_01:

Okay. So for years there was this group of patients who clearly had CMT symptoms. They had the weakness, the atrophy, all of it. But when they got genetic testing, the results came back with this frustrating label variants of unknown significance.

SPEAKER_00:

The dreaded VUS.

SPEAKER_01:

Right. Basically, the doctors were saying, We see a change in your DNA, but we have no idea if it's causing the disease or if it's just a random quark. These patients were in limbo.

SPEAKER_00:

That has to be so isolating. You know something's wrong, but science can't tell you what it is.

SPEAKER_01:

But then researchers started using these new biomarker techniques. They started mining the data and looking at metabolites, specifically sugar alcohols, and they found a pattern, a massive spike in something called sorbitol.

SPEAKER_00:

Sorbitol. Wait, like the artificial sweetener in chewing gum.

SPEAKER_01:

The very same. A sorbitol is a sugar alcohol. Normally your body processes it just fine. But they found these patients had a defect in an enzyme called SOD, which caused sorbitol to build up to toxic levels.

SPEAKER_00:

And that toxic buildup was what was killing the nerves.

SPEAKER_01:

Exactly. They finally had the mechanism. But here is the kicker, the thing that makes this story so incredible. There was already a drug in development for a totally different condition diabetic neuropathy that targeted that exact enzyme.

SPEAKER_00:

No way. So the treatment was effectively sitting on a shelf.

SPEAKER_01:

Hiding in plain sight. Because they identified the biomarker, the high soliditol, they could connect these undiagnosed patients to an existing drug. Suddenly they weren't unknowns anymore.

SPEAKER_00:

That is just. It's the power of metabolomics. It proves that mining this data isn't just an academic exercise, it unlocks actual cures.

SPEAKER_01:

It makes you wonder how many other cures are just sitting there in the data waiting for us to find the right measuring stick.

SPEAKER_00:

That is a very hopeful thought. But, and there's always a but none of this science happens in a vacuum. It requires patience to participate.

SPEAKER_01:

It does. And the source material highlights this massive shift in what is active patience. We're moving from the old way to the new way.

SPEAKER_00:

Aaron Powell Let's talk about the old way first, the nerve biopsy.

SPEAKER_01:

Which, frankly, is barbaric when you compare it to what we can do now. A nerve biopsy involves surgically removing a piece of nerve from your leg. Yeah. It's invasive, it requires anesthesia, leaves a scar, it can leave you with permanent numbness. And crucially, you can't do it twice.

SPEAKER_00:

Right. You can't go back six months later to see if the drug worked. The nerve is gone.

SPEAKER_01:

It's a one-time snapshot, and it comes at a high cost. The new way is fluids, blood, urine, plasma, which we can take over and over. But even cooler is the shift to digital biomarkers.

SPEAKER_00:

This is the wearable study HF is doing.

SPEAKER_01:

Yes. This is fascinating. Instead of going to a clinic once a year to walk down a hallway for 30 seconds, they strap sensors to your wrist and ankle.

SPEAKER_00:

And they track you for two weeks in the wild.

SPEAKER_01:

In the wild is the key phrase. Because in a clinic, you're performing. Adrenaline kicks in, you try your hardest. But what happens at 8 p.m. on a Tuesday when you're exhausted?

SPEAKER_00:

That's when you stumble. That's when the drop foot kicks in.

SPEAKER_01:

Exactly. The sensors catch that. They see how you manage stairs at work. They catch the little things that wouldn't happen in a clinic visit. It's turning real life into data.

SPEAKER_00:

Aaron Powell Yeah, the FDA loves this, right? Because it reflects actual quality of life.

SPEAKER_01:

Aaron Powell They do. It's what they call real-world evidence. But Alison Moore made a very passionate call to action about all this. We need the biobank.

SPEAKER_00:

The biobank dilemma. Explain this. Can't they just take one blood sample and use it forever?

SPEAKER_01:

Unfortunately, no. Every time a researcher runs an experiment, they use up a tiny bit of that blood or plasma. The sample is finite. It gets depleted.

SPEAKER_00:

Aaron Powell, so it's not a donate once and you're done kind of deal.

SPEAKER_01:

No. And more importantly, they need longitudinal data. They need a sample from you today, another in six months, another in a year. They have to prove the biomarker tracks with the disease over time.

SPEAKER_00:

Aaron Powell And if patients stop donating, the research just stops.

SPEAKER_01:

It grinds to a halt. And Dr. Rita Horveth brought up something straight out of science fiction about why these samples are so valuable. The skin-to-neuron pipeline.

SPEAKER_00:

This is mind-blowing.

SPEAKER_01:

She mentioned taking a skin sample, a small punch biopsy from the arm, and chemically reprogramming those cells to become stem cells and then turning those stem cells into neurons in a petri dish.

SPEAKER_00:

So they can test drugs on your specific neurons without ever touching your actual nerves.

SPEAKER_01:

Exactly. It's a personalized avatar of your disease.

SPEAKER_00:

Wow.

SPEAKER_01:

They can test thousands of compounds on a model of your genetic subtype to see what keeps those neurons alive.

SPEAKER_00:

But again, they can't do it if you don't show up and donate the sample.

SPEAKER_01:

That's the reality. The technology is here, but it needs the fuel. And the fuel is the patient's samples.

SPEAKER_00:

So let's wrap this up. We've covered a lot of ground here. We've gone from subjective pain scales to the high-tech world of MRI, fat fractions, and protein hunting.

SPEAKER_01:

Yeah, if we zoom out, we're looking at a three-tiered solution to this puzzle. One, imaging biomarkers, the MRI that gives us visual proof in 43 days. Two, liquid biomarkers, the proteins and metabolites like sorbital that reveal the molecular mechanism. And three, digital biomarkers, the wearables that tell the story of daily life.

SPEAKER_00:

And these three things together, they form that bridge that Allison Moore talked about.

SPEAKER_01:

That's the bridge. The bridge between basic research and actual FDA-approved treatments on the pharmacy shelf. Without biomarkers, that bridge is out.

SPEAKER_00:

It's hopeful. It really is. It feels like we are on the cusp of something big because the tools are finally getting sharp enough to see the problem.

SPEAKER_01:

I agree. But I want to leave the listener with a bit of a debate that came up among the experts. A little provocation to chew on.

SPEAKER_00:

Oh, I love a good scientific debate. What is it?

SPEAKER_01:

It's the tension between the universal and the specific.

SPEAKER_00:

Okay, lay it out.

SPEAKER_01:

So ideally, we would find a holy grail biomarker, one single protein, maybe neurofilament light chain that goes up in everyone with CMT, regardless of which of the 100 plus genetic types they have.

SPEAKER_00:

The golden ticket, one test for everyone.

SPEAKER_01:

Simple, clean. Pharmaceutical companies would love that. But as Dr. Ramirez and Dr. Horvath hinted, the biology might not be that kind. We might need a unique fingerprint, a specific biomarker for every single one of those genetic subtypes. A biomarker for type 1A, a different one for type 2A, another one for ASOR.

SPEAKER_00:

Which is a much, much harder mountain to climb. That's picking the lock one tumbler at a time.

SPEAKER_01:

It is. So the question is: will we find the master key, or do we have to forge a hundred different keys? The answer to that question is going to determine just how fast we can cure this thing.

SPEAKER_00:

That is a huge question. And I suspect the answer lies back in those biobanks we talked about.

SPEAKER_01:

It almost certainly does.

SPEAKER_00:

Well, that's all for today's deep dive. A huge thank you to the Hereditary Neuropathy Foundation for the source material. It's complex stuff, but man, is it important.

SPEAKER_01:

Absolutely.

SPEAKER_00:

Thanks for listening, everyone. Stay curious, and we'll catch you on the next one.