smartRNA Oligonucleotides for Reversible mRNA Stabilization

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Solution Overview

Problem

Current medical interventions for haploinsufficiency disorders and protein insufficiency disorders lack targeted and reversible methods to increase protein expression, and CRISPR-based strategies are non-reversible and dependent on non-human auxiliary proteins.

Innovation Solution

The use of small artificial RNA (smartRNA) oligonucleotides forming a ribonucleoprotein complex to increase 2'-O-methylation of the polyA-tail of target mRNA, delaying deadenylation and enhancing protein production.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CRISPR-based genome-editing strategies are used to mend the disease-causing allele, then the gene expression can be corrected, but the method is non-reversible and dependent on non-human auxiliary protein factors

Engineering Contradiction:

Improvegene expression correctionVSAvoidreversibility and human compatibility

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent uses an RNA-mediated intermediary mechanism where small artificial RNA molecules serve as mediators between the therapeutic agent and the target mRNA. This RNA intermediary allows for reversible gene expression modulation without requiring permanent genomic modification or non-human protein factors, thus resolving the contradiction between effective gene correction and reversibility/human compatibility

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent replaces the mechanical/protein-based CRISPR system with an RNA-based chemical system. Instead of using protein complexes and enzymatic machinery (CRISPR-Cas9), the invention uses small artificial RNA molecules that can modulate gene expression through RNA-RNA interactions, eliminating the need for non-human auxiliary proteins while maintaining therapeutic effectiveness

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Reliability

If contemporary oligonucleotide-based approaches are used to upregulate gene expression by exploiting unique features of the target mRNA, then protein levels can be increased, but these methods depend on the presence of specific features (upstream open reading frame, alternative polyadenylation sites, or miRNA binding sites) which are not generally present in all mRNAs

Engineering Contradiction:

Improveprotein expression upregulationVSAvoidapplicability to all mRNAs

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent creates a universal therapeutic mechanism that can be applied to any mRNA target regardless of its specific features. The small artificial RNA molecules can be designed to target any mRNA sequence through complementary base pairing, making the approach universally applicable to all mRNAs without requiring specific features like upstream open reading frames, alternative polyadenylation sites, or miRNA binding sites

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent changes the target parameter from specific mRNA structural features to the polyA-tail region, which is universally present in all eukaryotic mRNAs. By targeting the polyA-tail with small artificial RNA molecules, the invention achieves broad applicability across all mRNA targets while maintaining effective protein expression upregulation

Inventive Principle:

Principle #35Parameter changes

3Duration of action of stationary object

If methods that increase mRNA stability to elevate protein levels are used, then protein expression can be enhanced, but these methods require specific mRNA features that are not generally present in all mRNAs

Engineering Contradiction:

ImprovemRNA stabilityVSAvoidgeneral applicability to all mRNAs

Core Design Contradiction:

Duration of action of stationary objectVSAdaptability or versatility

Solution Approach 1:

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses an RNA-mediated intermediary mechanism where small artificial RNA molecules serve as mediators to stabilize target mRNA and enhance protein expression. This approach works universally across all mRNA targets by interacting with the conserved polyA-tail region, eliminating the need for mRNA-specific features

Inventive Principle:

Principle #24Intermediary (Mediator)

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

This approach effectively increases protein expression by stabilizing target mRNA, providing a targeted and reversible method for treating haploinsufficiency and protein insufficiency disorders.

Implementation Method 1

increasing the 2'-O-methylation level of one or more adenosines of the polyA-tail of the target mRNA, thereby delaying deadenylation of the targeted mRNA

Methodology Applied

Scientific Effect2'-O-methylation:

Data Source

PatentEP4711455A1Small artificial RNA (smartrna) oligonucleotide for modulating protein expression

Publication Date: 2026.03.18 AARHUS UNIV

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AI summary

The present invention relates to the use of small artificial RNA (hereafter referred to as "smartRNA") containing sequences creating secondary structure motifs similar to C/D box small nucleolar RNAs (snoRNAs), and antisense guide sequences, as a tool for targeted upregulation of protein expression. The smartRNAs assembles into a ribonucleoprotein (RNP) complex resulting in a smartRNP, increasing the 2'-O-methylation level of one or more adenosines of the polyA-tail of the target mRNA, thereby delaying deadenylation of the targeted mRNA, resulting in increased protein production.