Development of SARM1 Inhibitors to Treat Peripheral Neuropathies
A variety of environmental and genetic insults to peripheral nerves leads to acute injury or chronic disease, examples of which are chemotherapy-induced peripheral neuropathies (CIPN), diabetic peripheral neuropathy (DPN), and chronic genetic disorders such as Charcot-Marie Tooth. Despite ample evidence for axonal degeneration as the driver of disease progression, there are no therapies that specifically target axonal degeneration.
SARM1 has been identified as the central mediator of a cell-autonomous program of axonal degeneration and loss of function. In animal models of CIPN and DPN, SARM1 genetic deletion has shown robust axonal protection and preservation of neural function, thus confirming that SARM1 is an attractive target for development of a novel class of therapeutics for these disorders. Disarm is developing inhibitors of SARM1 to reproduce the SARM1 -/- axonal protective phenotype.
Neurofilament light chain (NF-L) is an axonal-specific cytoskeletal protein that is released as axons degenerate. It is increasingly being used as a clinical blood biomarker of central and peripheral neurodegeneration to measure disease progression and disease-modifying therapy effectiveness. We determined that NF-L is released after traumatic and chemically-induced axonal injuries in vitro and in vivo, and its release is SARM1-dependent.
Presented at the 2018 Peripheral Nerve Society Annual Meeting