Therapeutic applications targeting SARM1
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 for reducing axonal or synaptic degradation in a neuron, the method comprising:
selecting a neuron with or at an increased risk for developing axonal or synaptic degradation; and
contacting the neuron with an effective amount of a composition comprising a small interfering RNA (siRNA) that binds to sterile α/Armadillo/Toll-Interleukin receptor homology domain protein (SARM) mRNA for a time sufficient to inhibit SARM expression, thereby reducing axonal or synaptic degradation in the neuron.
2. The method of claim 1 , wherein the siRNA binds to SARM mRNA comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1, 3 and 5.
3. A method for reducing axonal or synaptic degradation in a subject with or at risk for developing axonal or synaptic degradation, the method comprising:
selecting a subject with or at an increased risk for developing axonal or synaptic degradation; and
treating the subject with an effective amount of a composition comprising a siRNA compound that binds to SARM mRNA for a time sufficient to inhibit SARM expression, thereby reducing axonal or synaptic degradation in the subject.
4. The method of claim 3 , wherein the subject at an increased risk for developing axonal or synaptic degradation is a subject that has experienced trauma of the CNS or PNS but that does not present symptoms of neurodegenerative disease.
5. The method of claim 3 , wherein the subject at an increased risk for developing axonal or synaptic degradation is a subject with diabetes but without diabetic neuropathy.
6. The method of claim 3 , wherein the subject at an increased risk for developing axonal or synaptic degradation is a subject scheduled to be exposed to a chemotherapeutic agent associated with the onset and/or development of neurodegeneration.
7. The method of claim 3 , wherein the subject at an increased risk for developing axonal or synaptic degradation is a subject scheduled to undergo or undergoing chemotherapy, or treatment with a toxin associated with neurodegeneration.
8. The method of claim 3 , wherein the subject has or is at an increased risk of neurodegenerative disease.
9. The method of claim 3 or 8 , wherein the axonal or synaptic degradation is in the central nervous system (CNS) or the peripheral nervous system (PNS).
10. The method of claim 9 , wherein the axonal or synaptic degradation is in the PNS.