SYNGAP1 Splicing Modulation to Increase Functional Protein Expression

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Solution Overview

Problem

There is a need for therapeutic agents that can increase SYNGAP1 protein or activity to treat conditions such as mental retardation, epileptic encephalopathy, or autism.

Innovation Solution

Compounds and methods are provided to modulate SYNGAP1 protein expression by using NSAE- or NSASS-modulating agents that interact with pre-processed mRNA transcripts to modulate splicing, thereby increasing the inclusion of canonical exons and excluding alternative exons, using agents like small molecules, polypeptides, or antisense oligomers to target specific splice sites.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional therapeutic approaches are used, then treatment of neurological conditions can be attempted, but they fail to effectively increase SYNGAP1 protein or activity

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoiddifficulty in achieving therapeutic effect

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent uses antisense oligomers as intermediary molecules that bind to specific RNA sequences to modulate splicing. These oligomers act as mediators between the therapeutic goal (increasing SYNGAP1) and the molecular mechanism (splicing regulation), enabling precise control of protein expression without directly interacting with the protein itself

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the molecular parameters of gene expression by modulating splicing events. By altering the splicing pattern to exclude alternative exons and include canonical exons, the treatment transforms the expression parameters of SYNGAP1, resulting in increased functional protein levels

Inventive Principle:

Principle #35Parameter changes

2Manufacturing precision

If splicing modulation is attempted without precise targeting, then SYNGAP1 expression might be affected, but off-target effects and lack of precision occur

Engineering Contradiction:

Improveprecision of splicing modulationVSAvoidcomplexity of targeting mechanism

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The antisense oligomers are designed to target specific segments or regions of the pre-mRNA molecule. By segmenting the targeting approach into discrete oligomer sequences that bind to specific splice site regions, the invention achieves precise modulation of splicing events without affecting other parts of the transcript

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent replaces complex mechanical or chemical splicing manipulation systems with a simpler molecular recognition system. The antisense oligomers use sequence-specific hybridization (a molecular recognition mechanism) to achieve precise targeting, substituting for more complex delivery or activation mechanisms

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Quantity of substance

If alternative exons are not excluded, then mRNA transcripts are produced, but functional SYNGAP1 protein is not sufficiently expressed

Engineering Contradiction:

Improveamount of functional proteinVSAvoidsimplicity of achieving protein expression

Core Design Contradiction:

Quantity of substanceVSEase of operation

Solution Approach 1:

The invention converts the potentially harmful presence of alternative exons (which lead to non-functional protein) into a benefit by using antisense oligomers to specifically exclude them. The alternative exons, which would normally disrupt protein function, are transformed into a controlled element where their exclusion becomes the mechanism for producing functional protein

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS20260055409A1Compounds and methods for treating human subjects

Publication Date: 2026.02.26 STOKE THERAPEUTICS INC

AI summary

Described herein are compounds and methods that can be used to treat a disease or condition by increasing SYNGAP1 protein.