Target mRNA Poly(A) Stabilization for Haploinsufficiency Expression

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Solution Overview

Problem

Existing methods fail to effectively regulate mRNA translation and treat haploinsufficiency disorders, which are characterized by a decrease in protein expression due to genetic mutations.

Innovation Solution

The use of nucleic acid agents comprising a complementary element that hybridizes with a target mRNA and a poly(A) region to enhance protein expression through post-transcriptional regulation, utilizing sequence and structural elements to recruit positive acting factors and stabilize the poly(A) tail.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If existing methods are used to regulate mRNA translation, then no effective regulation is achieved, but the poly(A) tail remains unstable and translation duration is limited

Engineering Contradiction:

Improveprotein expression levelVSAvoidpoly(A) tail stability

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent introduces a stabilizing element as an intermediary component that binds to the poly(A) tail and protects it from deadenylase enzymes. This mediator element acts as a shield between the poly(A) tail and the degrading enzymes, preventing premature removal and extending the functional lifespan of the mRNA for enhanced protein expression

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent modifies the poly(A) tail structure by adding a stabilizing element that changes its physical-chemical parameters. This modification alters the tail's susceptibility to enzymatic degradation, transforming it from an unstable structure subject to rapid removal into a stabilized structure that maintains its protective function over an extended period

Inventive Principle:

Principle #35Parameter changes

2Duration of action of stationary object

If the poly(A) tail is removed by deadenylase, then translation stops and mRNA is destroyed, but this limits the duration of protein production

Engineering Contradiction:

ImprovemRNA translation durationVSAvoidprotein output per mRNA

Core Design Contradiction:

Duration of action of stationary objectVSProductivity

Solution Approach 1:

The stabilizing element is incorporated into the mRNA structure in advance, before the mRNA enters the cytoplasm and encounters deadenylase enzymes. This preliminary protective measure ensures that when the mRNA is exposed to degradation enzymes, the poly(A) tail is already shielded and protected, preventing premature translation termination

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The stabilizing element serves as a protective cushion that absorbs the harmful effect of deadenylase enzymes before they can damage the poly(A) tail. This beforehand cushioning creates a buffer zone that protects the critical translation machinery from enzymatic degradation, extending the functional lifespan of the mRNA

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

3Productivity

If translational regulation is not implemented, then protein expression remains at natural levels, but therapeutic effect for haploinsufficiency disorders is insufficient

Engineering Contradiction:

Improveprotein expression levelVSAvoidnucleic acid agent structure

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The nucleic acid agent is segmented into distinct functional domains: a complementary element for target recognition and binding, a poly(A) tail for translation regulation, and a stabilizing element for enhanced durability. This segmentation allows each component to perform its specific function independently while working together to achieve therapeutic protein expression enhancement

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention creates a composite nucleic acid structure that combines different functional elements (complementary sequence, poly(A) tail, stabilizing element) into a single integrated agent. This composite structure leverages the strengths of each component to achieve both high protein expression and extended translation duration, providing therapeutic benefit for haploinsufficiency disorders

Inventive Principle:

Principle #40Composite materials

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

Enhances protein expression by stabilizing the poly(A) tail, thereby increasing the duration of mRNA translation and treating haploinsufficiency disorders such as 5q syndrome and Rett syndrome.

Implementation Method 1

a complementary element that hybridizes with a target mRNA

Methodology Applied

Scientific EffectHybridization: Chemical Bonding

Data Source

PatentUS20260071215A1Systems for enhancing target mRNA expression and uses thereof

Publication Date: 2026.03.12 JOHNS HOPKINS UNIVERSITY

AI summary

Provided herein are nucleic acid agents that are or comprise one or more nucleic acid molecules, together comprising (a) a complementary element that hybridizes with a target mRNA; and (b) a poly(A) element. In some embodiments, the target mRNA is an mRNA of an active allele of a gene associated with a disorder associated with a decrease in the expression of a protein from the mRNA, wherein the disorder is a haploinsufficiency disorder.