Dominant Negative SARM1 Variants for Preserving Axon Integrity
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Solution Overview
Problem
Current treatments are inadequate for targeting axonal degeneration, a hallmark of neurological disorders such as peripheral neuropathy, traumatic brain injury, and neurodegenerative diseases like Parkinson's disease and Amyotrophic Lateral Sclerosis, where axonal degeneration precedes symptom onset and widespread neuronal loss.
Innovation Solution
Development of dominant negative SARM1 polypeptides with specific amino acid changes at positions 189, 190, 193, or 194, and optionally 685, which inhibit SARM1 activity to prevent axon fragmentation after injury or damage, using vectors like adeno-associated virus (AAV) for delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for neurological disorders, then general symptom management is provided, but axonal degeneration cannot be effectively targeted or prevented
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions at positions 189, 190, 193, or 194 of the SARM1 protein sequence. These parameter changes (amino acid substitutions) create a dominant negative variant that specifically targets and inhibits SARM1-mediated axonal degeneration, transforming the treatment approach from general symptom management to targeted molecular intervention.
2Strength
If SARM1 activity is inhibited to prevent axon fragmentation, then axon integrity is preserved, but this requires specific molecular targeting that current treatments lack
Solution Approach 1:
The invention uses parameter changes in the form of specific amino acid substitutions (189, 190, 193, or 194) to create a dominant negative SARM1 protein that selectively inhibits SARM1 activity. This approach preserves axon integrity by blocking the degeneration pathway while the specific molecular targeting is achieved through precise amino acid parameter modifications rather than complex external delivery systems.
Data Source
Figure 1A~1B
Figure 1C
Figure 1D~1E
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.