SARM1 deletion protects axons in a model of inflammatory demyelination
ECTRIMS Online Library. Krauss R. 09/13/19; 278690; P1651
Raul Krauss
Raul Krauss
Contributions
Abstract

Abstract: P1651

Type: Poster Sessions

Abstract Category: Poster Session 3

R. Krauss, R. Hughes, T. Bosanac, R. Devraj, T. Engber

Disarm Therapeutics, Cambridge, MA, United States

Background: Axonal degeneration causes disease progression and accumulation of disability in multiple sclerosis (MS) and other neurodegenerative disorders. SARM1 is the central driver of an evolutionarily conserved program of axonal degeneration triggered by inflammatory, mechanical, metabolic, or chemical insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathy in MS. We have previously shown that SARM1-dependent axonal degeneration in traumatic nerve injuries can be assessed by measuring plasma levels of neurofilament light chain (NF-L), an axonal cytoskeletal protein released when axons degenerate and a well-established clinical biomarker of disability in MS.
Objectives: Assess axonal protection and therapeutic potential of SARM1 inhibition in inflammatory demyelination.
Methods: SARM1-/-, SARM1+/- and WT mice were subjected to experimental autoimmune encephalomyelitis (EAE) using MOG35-55 peptide. Disease scores were assessed daily, and plasma NF-L levels were measured at various timepoints to assess axonal injury. Spinal cord samples were processed for histological analysis of axonal structure.
Results: We determined plasma NF-L changes in EAE, a model of inflammatory demyelination characterized by axonal loss. In WT mice plasma NF-L began to rise concomitantly with onset of clinical symptoms, increased ~ 500% by peak of disease, and remained elevated for at least a week before beginning to decline. SARM1 genetic deletion reduced this increase in plasma NF-L by 76% at peak and 85% a week after peak disease. The peak of clinical symptoms was indistinguishable between WT and SARM1-/- mice, demonstrating that the inflammatory response was not affected by SARM1 genetic deletion. In this model where disability is primarily driven by inflammation, we also observed a modest benefit in clinical scores by AUC. Correlates between plasma NF-L and axonal damage were established by histological analysis.
Conclusions: SARM1 genetic deletion strongly protects axons in an inflammatory demyelinating environment in the CNS and supports the potential of SARM1 inhibition as an axonal protective therapy in MS. Disarm is developing small-molecule SARM1 inhibitors for central axonopathies, including multiple sclerosis and for a number of peripheral and ocular axonopathies.
Disclosure: Raul Krauss: employee and shareholder of Disarm Therapeutics
Robert Hughes: employee and shareholder of Disarm Therapeutics
Todd Bosanac: employee and shareholder of Disarm Therapeutics
Rajesh Devraj: employee and shareholder of Disarm Therapeutics
Thomas Engber: employee and shareholder of Disarm Therapeutics

Abstract: P1651

Type: Poster Sessions

Abstract Category: Poster Session 3

R. Krauss, R. Hughes, T. Bosanac, R. Devraj, T. Engber

Disarm Therapeutics, Cambridge, MA, United States

Background: Axonal degeneration causes disease progression and accumulation of disability in multiple sclerosis (MS) and other neurodegenerative disorders. SARM1 is the central driver of an evolutionarily conserved program of axonal degeneration triggered by inflammatory, mechanical, metabolic, or chemical insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathy in MS. We have previously shown that SARM1-dependent axonal degeneration in traumatic nerve injuries can be assessed by measuring plasma levels of neurofilament light chain (NF-L), an axonal cytoskeletal protein released when axons degenerate and a well-established clinical biomarker of disability in MS.
Objectives: Assess axonal protection and therapeutic potential of SARM1 inhibition in inflammatory demyelination.
Methods: SARM1-/-, SARM1+/- and WT mice were subjected to experimental autoimmune encephalomyelitis (EAE) using MOG35-55 peptide. Disease scores were assessed daily, and plasma NF-L levels were measured at various timepoints to assess axonal injury. Spinal cord samples were processed for histological analysis of axonal structure.
Results: We determined plasma NF-L changes in EAE, a model of inflammatory demyelination characterized by axonal loss. In WT mice plasma NF-L began to rise concomitantly with onset of clinical symptoms, increased ~ 500% by peak of disease, and remained elevated for at least a week before beginning to decline. SARM1 genetic deletion reduced this increase in plasma NF-L by 76% at peak and 85% a week after peak disease. The peak of clinical symptoms was indistinguishable between WT and SARM1-/- mice, demonstrating that the inflammatory response was not affected by SARM1 genetic deletion. In this model where disability is primarily driven by inflammation, we also observed a modest benefit in clinical scores by AUC. Correlates between plasma NF-L and axonal damage were established by histological analysis.
Conclusions: SARM1 genetic deletion strongly protects axons in an inflammatory demyelinating environment in the CNS and supports the potential of SARM1 inhibition as an axonal protective therapy in MS. Disarm is developing small-molecule SARM1 inhibitors for central axonopathies, including multiple sclerosis and for a number of peripheral and ocular axonopathies.
Disclosure: Raul Krauss: employee and shareholder of Disarm Therapeutics
Robert Hughes: employee and shareholder of Disarm Therapeutics
Todd Bosanac: employee and shareholder of Disarm Therapeutics
Rajesh Devraj: employee and shareholder of Disarm Therapeutics
Thomas Engber: employee and shareholder of Disarm Therapeutics

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