Splice Modulation for Targeted Gene Upregulation

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Solution Overview

Problem

Current technologies for modulating gene expression are limited in their ability to induce targeted gene upregulation, with few methods available to specifically increase or decrease gene expression effectively.

Innovation Solution

The use of splice modulation to alter the presence or absence of regulatory elements in RNA transcripts by targeting splicing signals, specifically through the inclusion or exclusion of exons containing upstream open reading frames (uORFs), to modulate gene expression by altering the presence or absence of regulatory elements in RNA transcripts.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If conventional gene modulation techniques (antisense, siRNA, CRISPR interference) are used, then targeted gene silencing is achieved, but targeted gene upregulation is limited

Engineering Contradiction:

Improvegene expression modulation capabilityVSAvoidtargeted gene upregulation effectiveness

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

Instead of using conventional methods that primarily silence genes, the invention inverts the approach by using splice modulation to remove negative regulatory elements (uORFs) from RNA transcripts. This inversion enables targeted gene upregulation rather than just silencing, as the removal of repressive elements allows the gene to be expressed at higher levels.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention extracts and removes specific regulatory sequences (uORFs) from the RNA transcript through splice modulation. By taking out these negative regulatory elements, the patent achieves targeted upregulation of the gene expression, separating the regulatory function from the coding sequence to enable independent control.

Inventive Principle:

Principle #2Taking out (Extraction)

2Reliability

If splice modulation is used to remove regulatory sequences, then targeted gene upregulation is achieved, but the complexity of the modulation process increases

Engineering Contradiction:

Improvetargeted gene upregulationVSAvoidsplice modulation process

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention uses splice modulation as an intermediary mechanism to achieve gene upregulation. Rather than directly manipulating the gene or using complex multi-step processes, the patent employs splice modulation as a mediator that selectively removes uORFs, simplifying the overall approach while maintaining targeted effectiveness.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Adaptability or versatility

If exons containing regulatory elements are included in the RNA transcript, then gene expression is modulated, but the presence of multiple regulatory elements increases the complexity of the transcript

Engineering Contradiction:

Improvegene expression controlVSAvoidtranscript structure

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The invention segments the RNA transcript into functional regions, specifically isolating exons that contain regulatory elements (uORFs) from the coding sequence. This segmentation allows for independent manipulation of regulatory elements, enabling precise control over gene expression without affecting the entire transcript structure.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20240344065A1method

Publication Date: 2024.10.17 OXFORD UNIVERSITY INNOVATION LTD

AI summary

The invention relates to modulating the expression or activity of a gene by modulating the presence of a regulatory element in the corresponding RNA transcript using a compound targeted to a splicing signal in the RNA transcript to induce splice modulation of one or more exons comprising the regulatory element.