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SARM1 inhibitors - a future cure for small-fiber neuropathy?
I'll write about a drug class called SARM1 inhibitors, which are in early drug development, and which could potentially treat autoimmune small-fiber neuropathy and many other neurodegenerative diseases in the future.
I like reading about such drugs in development, because it makes me optimistic that in the future there will be much better treatment options for many patients with rare nerve diseases. It's amazing how much we can fix, as long as there are enough money and intelligent minds going into it. 🌺
Disarm Therapeutics
The company, which is working on these drugs is called Disarm Therapeutics, a spin-off from the Washington University in St. Louis, Missouri, USA. The founders of the company are researchers, who have worked in academia for decades, during which time they discovered the molecule called SARM1 and its functions.
I think they are really onto something!✨
SARM1 inhibitors are a completely novel therapeutic approach, which may potentially treat a huge range of devastating neurological diseases.
What does SARM1 do?
The molecule SARM1 is present in all our nerves and functions like a switch, which controls whether or not a very important part of our nerve fibers (called the axon) degenerates/dies off. Axonal degeneration is the main driver of many neurological diseases. But let's take a step back...
What is an axon, and what is axonal degeneration?
I'm not a neuroscientist, so if you find that I write something incorrectly, please let me know and I'll fix it. Basically, we all have nerves running through our bodies, which originate in our brain (called the central nervous system, CNS), and run through the spinal cord, and then out into the periphery (peripheral nervous system, PNS) all the way into our toes and fingers.
The peripheral nerves are roughly divided into large peripheral nerve fibers, which control motor functions, and into the small nerve fibers, which control pain, vascular function and other autonomic (unvoluntary) functions in our bodies.
- Nerve fibers are long strands of nerve cells, also called neurons.
- Neurons transport electric stimuli through our bodies.
- If you touch something with your finger, this triggers an electric stimuli in a neuron, which then travels up to your brain so you can feel it.
- Axons are part of every neuron. They have the job to transmit information from one neuron to another, or from a neuron to muscles or glands.
- Axons can be up to meters long.
- Axonal degeneration means that axons die off.
- When axons die, neurons can't function.
- Depending on which type of neuron is affected (CNS, PNS, large fibers, small fibers etc), patients have different diseases.
- In small fiber neuropathy, axons of the small peripheral nerve fibers are affected.
Many diseases are caused by axonal degeneration
- Amyelotrophic lateral scrlerosis (ALS)
- Altzheimer's disease
- Multiple sclerosis (MS)
- Parkinson's disease
- Diabetic neuropathy
- Chemotherapy induced neuropathy
- Small-fiber neuropathy
- Traumatic nerve injuries
- Glaucoma
- Genetic forms of neuropathy
- and many more.......
All these diseases have different causes, like in my case an autoimmune reaction. For some of them we have no idea what the actual cause is. But they all have the following in common - that something induces the axons in specific neurons to die off, which causes detrimental symptoms. This is why these diseases are called neurodegenerative diseases.
SARM1 controls whether or not an axon dies or lives
Researchers have observed, that in many neurodegenerative diseases, axons die off much earlier than the rest of the neuron. They suspected that there must be a specific mechanism, which triggers this. However, researchers have tried and failed to identify what causes this axonal degeneration for decades.
During their academic careers, the founders of Disarm Therapeutics have identified SARM1, a molecule, which seems to trigger axonal degeneration once it gets activated. Here is a link to an scientific review on SARM1 inhibitors.
We all have SARM1 in our neurons, and it is usually kept inactive by our bodies. However, SARM1 gets activated by different pathological stimuli, and from what I read it's not entirely understood how. However, it was observed, that once it's activated it causes a cascade of reactions, starting with calcium influx into the cells, which eventually leads axons to die off. This process is called Wallerian degeneration (don't worry I've never heard about that before either 🧠🧠).
So those researchers figured that if you could inhibit SARM1 from activation, you may prevent this Wallerian degeneration and thus you could prevent axons from dying off. They developed a method to produce many different molecules, which may inhibit SARM1 from activation.
Where do SARM1 inhibitors stand in the development?
It is still very early days in the drug development process for SARM1 inhibitors. They have developed a bunch of molecules, which do inhibit SARM1 in lab tests. First pre-clinical (so not in humans) studies on cell lines and mice are looking promising. They were able to show that their drug candidates do prevent axons from degenerating when exposed to chemotherapy.
Of course it is still a very long way; only 1 in 10 drugs that are ever tested in humans eventually make it onto the market. But these ones just sound so fascinating, and I think given that they are developing a whole range of molecules they want to test, they have a valid chance. Big pharma has recognized their potential, and Eli Lilly bought them in fall 2020 for 135 million US Dollars.
We need a biomarker to measure axonal degeneration
Until today, there is no easy routine lab test that you can do, to test for axonal degeneration. However, it's impossible to develop a drug to fix axonal degeneration, without a means to measure if it works. So these researchers are about to fix this problem as well.
They found that whenever axons die off, they release a molecule called neurofilament light chain (NFL) into the blood stream. Neurofilaments are parts of the neuronal cytoskeleton, and are especially abundant in axons. The problem was though, that concentrations of this molecule are so low in blood that it was really hard to pick it up in a blood test.
However, they have now developed a test (a SIMOA assay), which can pick up tiny concentrations of NFL in the blood. And they were able to show that measured concentrations correlate with disease severity and prognosis in case of multiple sclerosis.
I'd love to be able to take this test
Unfortunately this test is not available routinely yet, because I'd really like to do it. It's suspected that in small fiber neuropathy, the axons of the small nerve fibers die off. But in reality nobody really knows what is going on.
At the moment I'm undergoing this new daratumumab therapy. The only way to see whether it works or not, is for me paying attention to my symptoms. And like I told you before - that can be very stressful for by dear friend BRAIN. 🧠🧠🧠🧠
With this test, I'd be able to see whether there is more/less NFL in the blood before / after treatment, which would show if the treatment is successful much before I'd notice a change in symptoms. I'm sure some time in the future this test will be a lot cheaper and available as a routine test, because it just makes so much sense to me. I think its a genius invention.
So let's keep our fingers crossed (🤞🏼🤞🏼) that some SARM1 inhibitors will roll through the drug development process smoothly. And that they will become available as powerful weapons in the fight against disabling neurological diseases in the semi-near future.
3 comments:
Very interesting! It sounds very promising. It’s a shame they aren’t further along in the process here. Hoping your current treatment will do the trick 🙏
That is exciting and promising news. I really hope this drug makes it to the market as there are so many patients that could benefit from it if it also works well in clinical trials.
Thank you for posting this. I’ve never heard of them but this gives me hope too!
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