Targeted Chloride Channel Expression for Localized Neuronal Modulation
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Solution Overview
Problem
Current methods for modulating electrophysiological activity of excitable cells, such as neurons and muscle cells, face challenges due to systemic side effects and the need for repeated administration of agonists or high doses to maintain physiological effects for chronic conditions, and there is a risk of immune responses from foreign proteins.
Innovation Solution
A vector comprising an expression cassette with a promoter linked to a nucleic acid encoding a subunit of a multimeric chloride channel is used to cause exogenous expression of a GlyR protein in mammalian cells, allowing modulation of electrophysiological activity with endogenous glycine as an agonist, potentially creating a constitutively active channel that does not require exogenous agonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ligands are administered systemically to modulate ion channels, then electrophysiological activity can be modulated, but widespread side effects occur
Solution Approach 1:
The patent employs local gene delivery methods (e.g., intrathecal injection, intracerebroventricular injection) to express chloride channels specifically in targeted neural tissues. This localized expression ensures electrophysiological modulation occurs only in the intended region, preventing widespread systemic side effects while maintaining therapeutic efficacy.
Solution Approach 2:
The patent introduces chloride channels (GluCl, GlyR) as intermediary proteins that can be selectively activated by specific ligands (ivermectin, glycine). These channels act as local mediators that convert systemic or locally-administered ligands into localized electrophysiological effects, reducing off-target effects compared to direct ligand administration.
2Reliability
If foreign proteins (e.g., GluCl) are expressed to silence neurons, then selective neuronal modulation is achieved, but immune responses may occur
Solution Approach 1:
The patent modifies the chloride channel proteins by introducing point mutations that alter their pharmacological properties. For example, mutations in GluCl allow selective activation by ivermectin with minimal activation by glutamate, while mutations in GlyR enable selective activation by sarcosine. These parameter changes enhance selective neuronal modulation while reducing immune recognition of foreign proteins.
Solution Approach 2:
The patent creates chimeric or modified protein structures by combining elements from different species or introducing specific mutations. These composite protein structures maintain functional selectivity while reducing immunogenicity compared to wild-type foreign proteins.
3Duration of action of moving object
If agonists (e.g., glycine) are administered repeatedly to maintain physiological effect, then chronic condition treatment is possible, but frequent administration is required
Solution Approach 1:
The patent uses gene delivery vectors to pre-express chloride channels in target tissues before agonist administration. This preliminary establishment of the molecular target allows for sustained physiological effects with reduced agonist dosing frequency, as the expressed channels remain available for prolonged activation.
Solution Approach 2:
The patent achieves continuous physiological modulation through sustained expression of chloride channels via gene delivery. The expressed channels provide ongoing capability for electrophysiological modulation, allowing continuous treatment effect without the need for frequent repeated administrations.
4Duration of action of moving object
If high doses of agonists are administered to treat persistent conditions, then therapeutic effect is maintained, but side effects increase
Solution Approach 1:
The patent achieves localized high-concentration activation of chloride channels at the target site through selective gene expression, while maintaining low systemic doses of activating ligands. This spatial differentiation allows persistent therapeutic effect at the target tissue without exposing the entire body to high doses and associated side effects.
Solution Approach 2:
The patent uses selectively-modified chloride channels as intermediaries that can be activated by low-dose, selective ligands. These engineered channels provide high sensitivity and selectivity, allowing persistent therapeutic effects to be achieved with minimal ligand dosing, thereby avoiding side effects associated with high-dose agonist administration.
Data Source
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AI summary
Certain embodiments of the invention provide a method of treating an excitable cell-related disease or condition in a mammal in need thereof, comprising administering to the mammal an effective amount of a vector comprising an expression cassette, wherein the expression cassette comprises a promoter operably linked to a nucleic acid encoding a subunit of a multimeric ion channel.