Degeneration of axons causes disability and progression in chronic and acute diseases of the central, ocular, and peripheral nervous systems such as multiple sclerosis, ALS, glaucoma, and peripheral neuropathies. Although substantial evidence indicates that these disorders are primarily the result of damage to axons, there are currently no therapies to prevent axonal degeneration.

To assess in vivo PK/PD of therapeutic candidates, we established translational models of CNS axonopathies in optic nerve crush, experimental acute encephalomyelitis (EAE), and cuprizone demyelination, and monitored SARM1-dependent biomarkers in wild type and SARM1-/- mutants.

We discovered that cADPR is a proximal biomarker of SARM1 enzymatic activity and also established that plasma neurofilament light chain (NF-L) is a biomarker of SARM1-dependent axonal degeneration. SARM1 genetic deletion prevented cADPR and plasma NF-L increases in an optic nerve crush model of CNS axonal injury. We are evaluating these two biomarkers, together with histological readouts, to assess the ability of SARM1 deletion to protect chronically demyelinated axons in cuprizone and EAE models.

SARM1 loss of function is a powerful mechanism of axonal protection in CNS axonopathies. Serum NF-L is increasingly being used as a clinical biomarker of neurodegeneration to measure disease progression and efficacy of disease-modifying therapies. cADPR and serum NF-L are SARM1-dependent biomarkers of axonal degeneration useful to monitor efficacy of SARM1 small molecule inhibitors.