A major news story from last year’s Peripheral Nerve Society (PNS) Annual Meeting was the promising research results from studies on the disease-modifying potential of SARM1 inhibition therapies. For the 2018 PNS meeting, we interviewed two experts from the Disarm scientific advisory board for their insights about peripheral neuropathies (PN) and how protecting nerve axons with SARM1 therapies could potentially benefit millions of patients.
Steven Scherer is the Ruth Wagner Van Meter and J. Ray Van Meter Professor of Neurology at the University of Pennsylvania and has been treating patients with neuropathies for nearly 40 years. His research efforts have focused on understanding the causes and treatments of peripheral neuropathies with an emphasis on inherited neuropathies.
Ahmet Hoke is Professor of Neurology and Neuroscience and Director for the Neuromuscular Division at Johns Hopkins. His clinical practice and research focuses on peripheral neuropathies with an emphasis on translational studies for developing therapies that prevent axonal degeneration and enhance peripheral nerve regeneration.
What is peripheral neuropathy?
Hoke: Simply put, peripheral neuropathies refer to the degeneration of the peripheral nerves. There are literally more than 100 different types of peripheral neuropathies based on their underlying causes that affect different populations of nerve fibers. As I tell my patients, think of your peripheral nerves as the wiring in your “house” that connects your skin and other organs to your central nervous system.
Scherer: These populations of nerve fibers have many different functions. For example, motor nerve fibers, which originate from motor neurons in the spinal cord, send out signals to activate muscles. Sensory nerve fibers have maybe a dozen different types of functions such as the perception of an itch or pain, movement of a joint or a vibration in your fingertips. And each of these modalities is coded by distinct, molecularly different sensory neurons. We also have autonomic neurons that regulate functions such as our heartbeat, blood pressure or rate of digestion apart from our conscious thoughts.
Hoke: Speaking of sensory nerves, there are actually two types of sensory fibers. One group is myelinated and connects the brain to your muscles and joints and helps you keep your balance. The myelination acts like insulation and therefore makes this group less vulnerable. The second type however, are small, unmyelinated fibers or nerve endings that go to the skin and are responsible for your perception of touch, temperature, irritation, etc. These are remote and more fragile and therefore are the source of symptoms for most peripheral neuropathies. When they are injured and degenerate they cause tingling, numbness and pain in the extremities of the body.
How prevalent are peripheral neuropathies?
Hoke: Although peripheral neuropathy is often viewed as an “orphan disease” of the neurodegeneration field, it is the most prevalent and affects more than 20 million people in the U.S. — more than Alzheimer’s, Parkinson’s and MS combined.
Epidemiological studies show that about 60% of diabetic patients will develop symptomatic neuropathy in their lifetimes and about 40% will have severe pain. It’s a huge problem that’s only going to get worse with the increasing incidence of obesity worldwide.
Scherer: An estimated seven million Americans have clinically evident neuropathies and several hundred thousand have genetic neuropathies, such as Charcot-Marie-Tooth disease (CMT), which is my area of specialty. People with CMT often suffer from childhood and experience symptoms including muscle weakness, and loss of sensation in the feet, the lower legs and other extremities, including the hands and arms.
Hoke: Chemotherapy-induced peripheral neuropathy (CIPN) is widely prevalent in cancer treatments. If a patient develops a moderate or severe neuropathy, an oncologist will usually stop using that drug and switch to another that may not be as effective. The incidence of CIPN for chemotherapy drugs commonly used to treat ovarian cancer and breast cancer is about 70 – 80% of which about half have persistent symptoms.
What is the greatest unmet need of patients who suffer from peripheral neuropathy?
Hoke: Pain in the feet is by far the most common complaint in particular in diabetes and chemotherapy patients. The loss of balance and injuries caused by numbness also are big problems. I tell patients to always make sure they check the bottom of their feet with a mirror every night and keep it clean because they could easily step on something sharp and develop a non-healing ulcer.
With advanced neuropathy, patients also can develop muscle weakness, especially with their ankles, that can cause them to trip and fall.
Scherer: Peripheral neuropathies rob people of the motor and sensory functions of their distal extremities. This causes weakness, pain and numbness, which often progresses by moving up the feet and hands. Severe neuropathies can also cause autonomic dysfunctions, such as the feet turning purple because of the loss of blood vessel control.
Hoke: Peripheral neuropathies rarely kill people but can make their lives miserable. Several patients told me they would rather have not had their chemotherapy treatments and risked their survival because the pain from their neuropathy was so severe.
What is the role of axonal degeneration in the development of and potential treatments for peripheral neuropathies?
Scherer: For most neuropathies, the loss of the nerve axons accounts for the clinical manifestations of the disease, even for demyelinating neuropathies, including the commonest form of CMT (CMT1A) and chronic inflammatory demyelinating polyneuropathy (CIDP), which is an acquired, inflammatory neuropathy.
Hoke: A key difference between peripheral neuropathy and other neurodegenerative diseases is that with PN there’s very little degeneration of the nerve cell body. Once neuronal cell death begins, it becomes more difficult to fix any problems because too much damage has occurred.
But with distal axonal degeneration diseases, the cell body is still relatively healthy for a prolonged period of time. If you can halt disease progression, peripheral nerves do have the capacity to regenerate axons. That’s what makes SARM1 inhibition so intriguing. If it can prevent further axonal degeneration, it’s possible that the natural regenerative capacity of the peripheral nerves would actually allow the axons to regenerate back to the target and regain lost function.
Scherer: At the end of the day, axonal loss is the cause of clinical disability, and today we have no tools to do too much about it except in rare instances where we can target the genetic or inflammatory cause of a neuropathy. But if we find SARM1 to be a universal common pathway of neuropathy, a drug that could block this path would be an incredible advance.
What are your thoughts on SARM1 as a target for researching new therapies in PN?
Hoke: CIPN is really the low-hanging fruit in the field in terms of therapeutic development. We know from preclinical animal data on partial ischemia to the central nervous systems that 1) drugs tend to work better if given before the injury occurs, and 2) it’s possible to make neurons resilient to degeneration.
CIPN is an acute condition and researchers can give the drug before the injury occurs, which makes clinical trial design so much simpler. Your outcome measure is going to be whether or not the patient develops neuropathy and it’s easy to quantify the extent of the neuropathy. This can all be done in a 3- to 6-month trial period. However, if a drug works to prevent acute CIPN there is a good chance that it can prevent the progression of more chronic diseases.
Scherer: We’re enthusiastic about preventing neuropathy as in the case of CIPN because it’s easier to detect this effect than it would be to detect the effect of treating someone who has a neuropathy, which would require you to measure the reduction in the rate of change.
Are there any new biomarkers that could expedite development of PN therapies and help to shorten the timeline for the chronic disease trials you mentioned earlier?
Hoke: Neurofilament light chain (NF-L) is probably going to be a game-changer in terms of measuring axonal degeneration. This protein is unique to neuronal cells, detectable at low concentrations in peripheral blood, and is emerging as a universal biomarker for axonal degeneration in many diseases.
Scherer: Having a blood biomarker would be incredibly useful as a complement to what we can learn from nerve conductions. If you could show that a drug prevented the decline in amplitude of sensory motor responses and at the same time prevented a bump upwards in NF-L blood levels, that would be persuasive evidence that the drug has in fact prevented axonal loss.
Hoke: If NF-L levels are elevated in presymptomatic patients, they could be treated before they become symptomatic. Every diabetic patient potentially could have their NF-L levels tested regularly along with their hemoglobin and A1C levels. If NF-L levels begin to rise, patients could be given a drug that protects their axons from degeneration. This prophylactic approach could be an effective way to treat all diabetics even before they develop neuropathy.
What is the current state of research on SARM1?
Hoke: We are gaining evidence that the SARM1 pathway is really a key modulator or regulator of axonal degeneration.
In diabetes, for example, hyperglycemia as a trigger of DPN has always been the prevailing concept. But in type 2 diabetes, there probably is significant dysmetabolism of the lipids, which could also lead to axonal degeneration through the SARM1 pathway. In a small preclinical study last year using a high fat diet model for type 2 diabetes, the SARM1 deficient arm did not develop neuropathy even though the mice had weight gain, while the control arm showed significant signs of axonal degeneration. This could indicate that SARM1 may affect how lipid dysmetabolism leads to axonal degeneration. SARM1 has been shown by several academic groups to be implicated in CIPN caused by taxols, vinca alkaloids and proteasome inhibitors. Our lab has worked on a couple of unpublished studies where we tested two CIPN neuropathy models, we saw broad protection regardless of the initiating mechanisms of axonal degeneration.
The idea is to use the knowledge gained from CIPN both in the animal models as well as clinical trials to better understand and expand the model to other forms of neuropathies.
Scherer: Although preventing axonal loss with a SARM1 knockout in an inherited or acquired demyelinated neuropathy has not yet been directly tested, I and many others would be interested in this research. If such a study shows efficacy in an animal model, I would be optimistic that it might work in people because, at least for genetic neuropathies, the animal models are excellent.
What do you find attractive about SARM1’s potential as a therapeutic approach for PN?
Hoke: One of the difficult problems with neuropathic pain is that it can involve multiple mechanisms and molecular pathways, even in a single patient. That’s a big reason why there aren’t any good molecular-targeted neuropathic pain treatments.
With SARM1, you have a pathway that works for a whole set of neuropathies. What makes it attractive is that this pathway can be a target almost independent of the injury. If you can prevent axonal degeneration you can prevent activation of pain without having to deal with the complexities of treatment.
Scherer: As a student of inherited neuropathies, I’ve always felt that it’s important to figure out the genetic causes of individual’s neuropathies and search for their molecular causality. But if, as the initial SARM1 preclinical research has shown, axonal degeneration can be targeted and prevented in various clinical settings, this might enable one to treat neuropathies even without understanding the molecular pathogenesis.
If you go to the PNS meeting in Baltimore this year, I think you will find great enthusiasm for what SARM1 inhibition might do. People who have the scientific background to appreciate where this came from understand why SARM1 inhibition could be so profound.