NeuroVoices: Michael Coleman, PhD, on Understanding Programmed Axon Death and Its Therapeutic Potential

Axonal degeneration is a hallmark of numerous neurologic diseases, yet the molecular pathways driving axon loss have only recently emerged as potential therapeutic targets. Among the most notable discoveries has been the identification of programmed axon death, an intrinsic cellular pathway that actively dismantles injured or stressed axons through activation of sterile alpha and TIR motif-containing protein 1 (SARM1). The pathway has attracted increasing attention as researchers explore whether interrupting axon degeneration could slow disease progression across a range of neurodegenerative and neuromuscular disorders.

At the 2026 Peripheral Nerve Society (PNS) Annual Meeting, held June 13-16 in Maastricht, Netherlands, Michael Coleman, PhD, presented a session focused on programmed axon death and its relevance to human disease. Over the past two decades, Coleman's work has helped define the molecular mechanisms underlying axon degeneration, including the roles of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and SARM1, which together regulate axonal survival and degeneration. These discoveries have laid the foundation for emerging therapeutic programs aimed at preserving axons in diseases such as amyotrophic lateral sclerosis (ALS), chemotherapy-induced peripheral neuropathy (CIPN), Charcot-Marie-Tooth disease (CMT), and other neurodegenerative conditions.

In a new iteration of NeuroVoices, Coleman discussed the biologic rationale behind targeting programmed axon death, the current status of SARM1 inhibitor development, and the importance of moving beyond traditional animal models toward human genetics, biomarkers, and patient-derived cellular systems. He also highlighted the challenges facing clinical development programs and outlined where future research efforts may have the greatest impact.

NeurologyLive: For clinicians who may be less familiar with the concept, what is programmed axon death and why is it becoming increasingly relevant across neurology?

Michael Coleman, PhD: Programmed axon death is a mechanism that exists in all of our axons, both in the central and peripheral nervous systems, that appears to be designed to kill axons. You might ask why we would evolve to have such a mechanism. One hypothesis is that it serves as a defense against viruses spreading through the nervous system using axonal transport, although that remains an active area of investigation.

When this mechanism becomes activated, however, it can contribute to neurological disease. ALS is certainly one candidate. Chemotherapy-induced peripheral neuropathy is another, and we're very interested to see whether that extends to Charcot-Marie-Tooth disease and other motor neuronopathies.

What were the major themes of your presentation at PNS 2026?

My laboratory has spent many years studying animal models of neurological disease, as well as primary neuronal cultures, primarily from mice. That work has taught us a tremendous amount, and many other groups have contributed valuable findings through similar approaches.

At the same time, I believe there is a limit to what animal models alone can tell us. Ultimately, we need to move toward approaches that incorporate human data. That's why we're increasingly focusing on human genetics, where the amount of available sequencing data has expanded dramatically, as well as human biomarkers and patient-derived neurons generated from stem cells.

Animal models absolutely still have a role. In fact, we're collaborating with colleagues using those approaches. But they should be viewed as one part of a broader spectrum that includes human genetics, biomarkers, and patient-derived systems when deciding which diseases and pathways are most appropriate to advance into clinical trials.

SARM1 has emerged as a major therapeutic target in this space. Where does development of SARM1-targeted therapies currently stand?

SARM1 is an NAD-degrading enzyme that, when activated, kills axons and can also kill neuronal cell bodies. In axons, it is regulated by NMNAT2, an NAD-synthesizing protein. When NMNAT2 levels fall, NMN accumulates, activates SARM1, and triggers axon degeneration.

We think this biology may help explain why many axonal disorders are length dependent. NMNAT2 is an unstable protein that must be transported along the axon. In very long axons, less of it reaches the distal regions, making those areas particularly vulnerable to SARM1 activation.

There are currently clinical trials targeting SARM1 enzyme activity. Some programs have successfully completed phase 1 testing and are now moving into or preparing for phase 2 studies, particularly in ALS and chemotherapy-induced peripheral neuropathy.

What challenges do you foresee as these therapies move into later-stage clinical development?

There are several important challenges. The first is safety. Some SARM1 inhibitors have successfully completed phase 1 studies, which is encouraging, but there remain theoretical concerns regarding low-level SARM1 activation under certain circumstances. To date, these concerns have not translated into clinical symptoms, but they continue to be monitored.

The second major challenge is disease heterogeneity. ALS is a good example. There are dozens of known genetic causes, along with many environmental factors that likely contribute. It's quite possible that SARM1 inhibition could produce meaningful benefit in some patients but not others. If that's the case, the overall treatment signal could become diluted across a heterogeneous study population.

Chemotherapy-induced peripheral neuropathy may present fewer challenges in that regard because preclinical evidence suggests that SARM1 inhibition can be effective across multiple chemotherapy agents. Nevertheless, translating those findings from animal models into human disease remains a significant hurdle.

Perhaps most importantly, we need biomarkers. We need reliable biomarkers that tell us whether SARM1 is active in a particular patient, both before and during treatment. Those could be fluid biomarkers or other biologic indicators, but they will be critical for moving the field forward.

Do you envision SARM1 inhibition becoming a standalone treatment strategy or part of combination approaches?

That's a very important question. In many diseases, the primary cause may involve impaired axonal transport, mitochondrial dysfunction, or disrupted protein synthesis. Those upstream events may ultimately activate SARM1, but they also produce other downstream consequences.

If you block SARM1, you may preserve the axon, but other disease-related abnormalities could still remain. In those situations, SARM1 inhibition may provide an important disease-modifying effect while still requiring additional therapies to address other aspects of the pathology.

That said, there are rare disorders caused directly by mutations in SARM1 itself or in its regulator, NMNAT2. In those cases, blocking SARM1 could have a profound therapeutic effect. In animal models of NMNAT2 deficiency, we've rescued mice from neonatal death and restored them to a normal lifespan by eliminating SARM1 activity. That's about as strong a rescue as one can imagine.

Although these patients are extremely rare, they may serve as important positive controls for understanding whether these therapies are working and how best to apply them across other diseases.

Looking ahead, where should future research efforts focus?

I would return to those ultra-rare patients with mutations that directly activate SARM1 or disrupt NMNAT2. Although they are extraordinarily uncommon, we can learn a tremendous amount from studying them.

These patients offer opportunities to identify biomarkers, generate patient-derived neurons, directly observe evidence of SARM1 activation, and test therapies in biologically relevant systems. They may ultimately help us establish proof of mechanism in humans.

Once we know these drugs are working in people somewhere, we can then begin extending them into broader disease populations. Human genetics, biomarkers, and carefully selected patient groups will be critical in determining where these therapies have the greatest chance of success.

Transcript edited for clarity. Click here for more PNS 2026 coverage.