Engineered Polynucleotides for Timed mRNA Expression Control

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Solution Overview

Problem

Existing mRNA therapies face challenges in tightly regulating and consistently controlling mRNA expression timing, which is crucial for optimal therapeutic efficacy and minimizing side effects in applications such as protein engineering, immunotherapy, and gene therapies.

Innovation Solution

A composition comprising a first polynucleotide with a repressor binding element and an open reading frame encoding a first polypeptide, and a second polynucleotide with a repressor that binds to the element and a destabilization domain, which controls mRNA expression timing by reducing translation and enhancing repressor degradation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If mRNA expression is controlled using traditional methods, then expression can be achieved, but temporal precision and consistency of expression timing cannot be tightly regulated

Engineering Contradiction:

Improvetemporal precision of mRNA expressionVSAvoidconsistency of expression timing

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The system employs a feedback mechanism where the repressor protein continuously monitors the presence of the binding element on the mRNA and adjusts translation accordingly. When the repressor is present, it binds to the binding element and suppresses translation; when the repressor is degraded or removed, translation is activated. This feedback loop ensures precise temporal control and consistent timing of mRNA expression.

Inventive Principle:

Principle #23Feedback

Solution Approach 2:

The system dynamically controls mRNA translation by introducing a destabilization domain to the repressor protein, which allows for time-limited repression. The repressor's half-life can be precisely controlled through the destabilization domain, enabling dynamic adjustment of the timing window. This dynamic approach replaces static control mechanisms with adjustable temporal parameters, achieving both precision and consistency in expression timing.

Inventive Principle:

Principle #15Dynamics

2Duration of action of moving object

If repressor protein is used to control mRNA translation, then temporal control is achieved, but repressor stability and duration of action become difficult to regulate precisely

Engineering Contradiction:

Improveduration of repressor actionVSAvoidprecision of repressor stability control

Core Design Contradiction:

Duration of action of moving objectVSManufacturing precision

Solution Approach 1:

The system changes the stability parameter of the repressor protein by incorporating a destabilization domain with a controlled half-life. This allows the duration of repressor action to be precisely tuned by selecting different destabilization domain variants or modifying their degradation rates. The parameter change approach enables independent control of repressor stability without affecting other aspects of the system.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The repressor protein is constructed as a composite entity combining a functional domain (for binding to the mRNA binding element) with a destabilization domain (controlling protein stability). This composite structure allows independent optimization of binding affinity and stability characteristics, achieving precise control over the duration of repressor action while maintaining reliable temporal control.

Inventive Principle:

Principle #40Composite materials

3Reliability

If tight temporal control of mRNA expression is implemented, then therapeutic efficacy is enhanced, but system complexity increases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidcomplexity of control system

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The control system is segmented into distinct functional modules: the mRNA with its binding element, the repressor protein with its binding domain and destabilization domain, and the translation machinery. This segmentation allows each component to be independently designed, optimized, and regulated. The modular approach reduces overall system complexity while enabling tight temporal control through coordinated interaction of simple, well-defined components.

Inventive Principle:

Principle #1Segmentation

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 system allows precise temporal control of mRNA expression, enhancing therapeutic efficacy and reducing side effects by ensuring proteins are expressed at the right time and location, applicable in protein engineering, immunotherapy, and gene therapies.

Implementation Method 1

the destabilization domain comprises a ubiquitin tag

Methodology Applied

Scientific EffectUbiquitin tag degradation:

Implementation Method 2

binding of the repressor to the repressor binding element reduces translation of the first polypeptide from the first polynucleotide

Methodology Applied

Scientific EffectProtein-RNA binding:

Data Source

PatentUS20260035707A1Engineered polynucleotides for temporal control of expression

Publication Date: 2026.02.05 MODERNATX INC

AI summary

The disclosure features compositions, systems, and uses thereof, comprising polynucleotide(s) encoding target molecule(s), and polynucleotide(s) encoding repressor(s) or timer(s). The repressor(s) or timer(s) delay expression of the target molecule(s).