Therapeutic Applications Targeting SARM1

Abstract

The present disclosure provides methods for reducing axonal and/or synaptic degradation in neurons by modulating sterile α/Armadillo/Toll-Interleukin receptor homology domain protein (SARM) activity and/or expression.

1 . A method reducing axonal and/or synaptic degradation in a neuron, the method comprising:
 selecting a neuron with or at risk for axonal and/or synaptic degradation; and   contacting the neuron with an effective amount of a composition that inhibits sterile α/Armadillo/Toll-Interleukin receptor homology domain protein (SARM) activity and/or expression for a time sufficient to inhibit SARM activity and/or expression, thereby reducing axonal and/or synaptic degradation in the neuron.   
     
     
         2 . A method for reducing axonal and/or synaptic degradation in a subject with or at risk for developing axonal and/or synaptic degradation, the method comprising:
 selecting a subject with or at risk for developing axonal and/or synaptic degradation; and   treating the subject with an effective amount of a composition that inhibits SARM activity and/or expression for a time sufficient to inhibit SARM activity and/or expression, thereby reducing axonal and/or synaptic degradation in the subject.   
     
     
         3 . The method of  claim 2 , wherein the subject has or is at risk of neurodegenerative disease. 
     
     
         4 . The method of  claim 2  or  3 , wherein the axonal and/or synaptic degradation is in the central nervous system (CNS) and/or the peripheral nervous system (PNS). 
     
     
         5 . The method of  claim 4 , wherein the axonal and/or synaptic degradation is in the PNS. 
     
     
         6 . The method of  claim 5 , wherein the subject has diabetes. 
     
     
         7 . The method of  claim 6 , wherein the subject has diabetic neuropathy. 
     
     
         8 . The method of  claim 5 , wherein the subject is scheduled to receive chemotherapy. 
     
     
         9 . The method of  claim 5 , wherein the subject is receiving chemotherapy or has received chemotherapy. 
     
     
         10 . A method for identifying a compound that inhibits SARM activity and/or expression, the method comprising:
 providing SARM;   contacting the SARM with a test compound; and   determining whether the test compound interacts with or binds to SARM, wherein a test compound that interacts or binds with SARM is a candidate compound that inhibits SARM activity and/or expression.   
     
     
         11 . The method of  claim 10 , wherein SARM and the test compound are contacted in silico. 
     
     
         12 . The method of  claim 10  or  11 , wherein SARM and the test compound are contacted in vitro. 
     
     
         13 . The method of  claim 10 , wherein determining whether the test compound interacts with or binds to SARM is performed directly. 
     
     
         14 . The method of  claim 10 , wherein determining whether the test compound interacts with or binds to SARM is performed indirectly. 
     
     
         15 . A method for identifying a compound that inhibits SARM activity and/or expression, the method comprising:
 providing a sample comprising SARM;   contacting the sample with a compound; and   measuring the transcriptional activity of SARM in the sample, wherein a decrease in the transcriptional activity of SARM in the sample in the presence of the compound indicates that the compound is a candidate compound that inhibits SARM activity and/or expression.   
     
     
         16 . A method for identifying a compound that inhibits SARM activity and/or expression, the method comprising:
 contacting a neuron with the candidate compound of  claim 10  or  claim 15 ;   axotomizing the neuron; and   determining whether axonal and/or synaptic degradation is altered in the presence of the candidate compound relative to axonal degradation in the absence of the compound, wherein a decrease in axonal and/or synaptic degradation indicates that the candidate compound is a compound that inhibits SARM activity and/or expression.   
     
     
         17 . The method of  claim 16 , further comprising:
 obtaining the compound;   administering the compound to an animal model of neurodegenerative disease; and   assessing the degenerative disease in the animal in the presence of the compound, wherein a decrease in degenerative disease in the presence of the compound indicates that the compound inhibits SARM activity and/or expression.