KCC2 Upmodulation for Spinal Cord Injury Recovery

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Solution Overview

Problem

Current treatments for spinal cord injuries are limited in promoting functional recovery, particularly in cases of anatomically incomplete injuries where spared axons fail to mediate functional recovery, and there is a need for better understanding of axon regeneration.

Innovation Solution

The use of agents that upmodulate neuron-specific K+—Cl− co-transporter (KCC2) activity, inhibit Na+/2Cl−/K+ co-transporter (NKCC), and reduce excitability in inhibitory interneurons, such as through Gi-DREADD expression, to restore stepping function in mice with severe spinal cord injuries, along with compositions comprising these agents for therapeutic use.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapeutics are used for spinal cord injury, then treatment is provided, but functional recovery is not regenerated

Engineering Contradiction:

Improvefunctional recoveryVSAvoidtreatment effectiveness

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent changes the physiological parameters of the spinal cord by modulating chloride transport through KCC2 upregulation and NKCC inhibition. This alters the electrochemical gradient and neuronal excitability, transforming the non-functional spinal cord state into a functional state capable of supporting stepping movements

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces intermediary molecules (KCC2 upmodulating agents, NKCC inhibitors) that mediate between the damaged spinal cord structure and functional recovery. These agents act as intermediaries to restore proper chloride gradients and neuronal excitability without directly regenerating axons

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If agents that upmodulate KCC2 are administered, then stepping function is restored, but treatment complexity increases

Engineering Contradiction:

Improvestepping function restorationVSAvoidtreatment regimen

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent employs agents with multiple functions: KCC2 upmodulating agents simultaneously increase KCC2 expression and activity, while NKCC inhibitors both reduce NKCC activity and enhance the net effect of KCC2. This multi-functionality consolidates multiple therapeutic effects into single agents, reducing overall treatment complexity

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If spinal circuits are transformed to functional states, then brain-derived commands are relayed, but mechanism complexity increases

Engineering Contradiction:

Improvecommand relay functionVSAvoidcircuit transformation mechanism

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent replaces complex mechanical/structural axon regeneration with a biochemical/electrophysiological mechanism. By modulating chloride transport and neuronal excitability, the treatment achieves functional recovery through chemical means rather than requiring physical axon regrowth, simplifying the overall mechanism

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS20210254101A1Methods for treating spinal cord injury

Publication Date: 2021.08.19 CHILDRENS MEDICAL CENT CORP

AI summary

Described herein are methods and compositions for treating a spinal injury. Aspects of the invention relate to administering to a subject an agent that upmodulates KCC2. Another aspect of the invention relates to administering to a subject an agent that that reduces excitability of inhibitory interneurons. Compositions comprising these agents are additionally described herein.