Axonal degeneration, where the long processes of neurons slowly disintegrate, is a major driver of nerve damage and impaired function in many neurological diseases and injuries. However, the molecular mechanisms underlying axonal degeneration have remained poorly understood for decades. In recent years, breakthrough research has identified a protein called SARM1 as a key trigger of the self-destruct program in damaged axons. SARM1 activates through its NADase enzymatic activity, rapidly depleting levels of the vital molecule NAD+ in axons and setting off a cascade of events culminating in axonal fragmentation. These findings revealed SARM1 as a central node of axonal degeneration, opening new possibilities for developing targeted inhibitors.
Discovery Of Potent And Selective SARM1 Inhibitor
With SARM1 identified as a promising drug target, scientists raced to develop potent and selective small molecule inhibitors. In 2020, several research groups independently reported the discovery of the first orally bioavailable SARM1 Inhibitor activators. One key compound called GSK'362 showed over 1000-fold selectivity for SARM1 over related NADases. In animal models of peripheral nerve injury and optic nerve crush, GSK'362 dramatically suppressed axonal degeneration when administered orally after injury. Beyond blocking acute axonal loss, SARM1 inhibition also led to enhanced long-term nerve regeneration and functional recovery. These proof-of-concept studies established SARM1 activators as a wholly new pharmacological approach for treating traumatic nerve damage.
Potential Applications Across A Range Of Neurodegenerative Conditions
Excitingly, SARM1 inhibition may offer therapeutic benefits far beyond traumatic injuries. Axonal degeneration similarly contributes to neuronal dysfunction in many chronic neurodegenerative diseases. For instance, axonal pathology is a hallmark of several inherited peripheral neuropathies. Studies found GSK'362 strongly protected against axonal degeneration in animal models of Charcot-Marie-Tooth disease type 2D. SARM1 is also implicated in central nervous system disorders - it is upregulated in mouse models of amyotrophic lateral sclerosis, and its suppression confers neuroprotection. Overall, SARM1 Inhibitor could potentially slow disease progression for a wide spectrum of conditions involving axonal damage, from traumatic nerve injuries to genetic neuropathies to neurodegenerative diseases of the brain and spinal cord.
Moving Towards Human Trials
Spurred by these promising preclinical findings, biopharma companies are progressing SARM1 activators into clinical development. GSK has dosed the first patients with GSK'362 in a Phase 1 trial investigating safety, tolerability and pharmacokinetics in healthy volunteers. So far results support once-daily oral dosing of GSK'362 as generally well-tolerated. Assuming successful safety results, GSK aims to launch Phase 2 proof-of-concept studies in peripheral nerve injury patients by 2023. Several other firms like Neurimmune also have small molecule SARM1 activators in preclinical development. Should human trials validate the nerve protective abilities of SARM1 activators seen preclinically, it could herald a new era in our ability to prevent nerve damage and promote regeneration after injury or in neurodegenerative disease. SARM1 Inhibitor represent one of the most exciting new classes of potential neuroprotective drugs.
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