Dominant Negative SARM1 Variants for Axon Degeneration Inhibition
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Solution Overview
Problem
Current treatments are lacking for neurological disorders characterized by axonal degeneration, such as peripheral neuropathies, traumatic brain injury, and neurodegenerative diseases like Parkinson's and Alzheimer's, as they do not effectively target the molecular underpinnings of axon degeneration.
Innovation Solution
Development of dominant negative SARM1 molecules, encoded by nucleic acids, which inhibit SARM1 activity through mutations in specific regions, such as amino acids 175 to 200 and 675 to 700, to prevent or ameliorate axonal degeneration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for neurological disorders, then general symptom management is provided, but they fail to effectively target the molecular underpinnings of axon degeneration
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions at defined positions (189, 190, 193, 194, 570, 685) of the SARM1 protein to create dominant negative variants that selectively inhibit SARM1-mediated axon degeneration while preserving other SARM1 functions, thereby achieving targeted molecular intervention
Solution Approach 2:
The patent segments the SARM1 protein into specific regions of interest (amino acid positions 189-194 and 570-685) and introduces mutations in these segmented regions to achieve selective inhibition of axon degeneration pathways while maintaining other SARM1 activities
2Reliability
If dominant negative SARM1 molecules with multiple mutations are created, then inhibition of SARM1 activity is enhanced, but molecular complexity increases
Solution Approach 1:
The patent applies local quality by introducing mutations at specific local positions (189, 190, 193, 194, 570, 685) of the SARM1 protein rather than throughout the entire sequence, creating dominant negative variants with localized modifications that achieve high inhibition efficacy while minimizing overall molecular complexity
Solution Approach 2:
The patent creates composite molecular structures by combining wild-type SARM1 regions with mutated dominant negative regions, resulting in hybrid protein molecules that exhibit enhanced inhibition properties while maintaining structural integrity and manageable complexity
Data Source
AI summary
The present invention provides compositions useful as inhibitors of SARM1 activity, pharmaceutical compositions thereof, and methods of using the same. The present invention provides dominant negative SARM1 molecules useful for treating a neurodegenerative or neurological disease or disorder, pharmaceutical compositions thereof, and methods of using the same.