Exon Skipping Oligomer Conjugates for Dystrophin Restoration

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Solution Overview

Problem

Existing antisense oligomers are ineffective in up-regulating the production of native proteins or compensating for mutations that cause premature termination of translation, such as in Duchenne muscular dystrophy, as they either promote target mRNA decay or block translation, which is not suitable for conditions where functional protein production is desired.

Innovation Solution

Development of antisense oligomer conjugates comprising a 22-subunit antisense oligomer moiety with a cell-penetrating peptide (CPP) linker, specifically designed to target exon 45 of the dystrophin gene, inducing exon skipping and restoring the reading frame for dystrophin production.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional antisense oligomers are used to target mutant mRNA, then gene expression inhibition is achieved, but the defective gene transcript is subjected to targeted degradation or steric inhibition which prevents protein production

Engineering Contradiction:

Improvegene expression inhibitionVSAvoidmRNA decay or translation block

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

Instead of degrading or blocking the mutant mRNA as conventional antisense oligomers do, this invention uses antisense oligomers to induce exon skipping during splicing, thereby removing the mutant exon from the transcript and restoring the reading frame. This inverted approach converts the harmful effect of mutation into a beneficial outcome by leveraging the splicing machinery to create functional protein.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention converts the harmful effect of nonsense or frame-shifting mutations into a benefit by using antisense oligomers to trigger exon skipping. The mutant exon, which would normally cause premature termination, is instead removed through splicing modulation, allowing the remaining exons to form a functional reading frame and produce viable protein.

Inventive Principle:

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

2Reliability

If antisense oligomers promote target mRNA decay or block translation, then gene down-regulation is achieved, but functional protein production is prevented

Engineering Contradiction:

Improvegene down-regulationVSAvoidfunctional protein production

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

Rather than suppressing gene expression through mRNA decay or translation blocking, this invention inverts the approach by using antisense oligomers to modulate splicing. The oligomers bind to pre-mRNA and induce exon skipping, which removes mutant exons and restores the reading frame, thereby enabling functional protein production from previously non-functional transcripts.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention changes the mechanism of action from transcriptional or translational suppression to splicing modulation. By altering the splicing parameters through antisense oligomer binding, the system transitions from producing non-functional proteins to producing functional, truncated proteins with restored reading frames.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If conventional antisense chemistry is used, then specific gene down-regulation is achieved, but it cannot compensate for mutations that induce premature termination

Engineering Contradiction:

Improvespecific gene down-regulationVSAvoidcompensation for premature termination mutations

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The invention makes the antisense oligomer system multi-functional by enabling it to perform both gene down-regulation and compensation for premature termination mutations. Through exon skipping mechanism, the same oligomer chemistry can restore reading frames in mutant transcripts while maintaining specificity for target exons, thereby expanding the therapeutic applicability.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The invention inverts the traditional antisense approach by using exon skipping rather than direct mRNA degradation. This inversion allows the system to compensate for premature termination mutations by removing the mutant exon and restoring the reading frame, thereby producing functional protein from previously non-functional transcripts.

Inventive Principle:

Principle #13The other way round (Inversion)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The antisense oligomer conjugates effectively induce exon skipping, leading to the production of a functional, truncated dystrophin protein, improving muscle function and providing therapeutic benefits for Duchenne muscular dystrophy.

Implementation Method 1

an antisense oligomer of 22 subunits in length capable of binding a selected target to induce exon skipping in the human dystrophin gene, wherein the antisense oligomer comprises a sequence of bases that is complementary to an exon 45 target region

Methodology Applied

Scientific EffectComplementary base pairing: