mRNA UTR Optimization for Translation and Expression Durability

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Solution Overview

Problem

Existing mRNA technologies focus on optimal sequence design for the open reading frame (ORF) but fail to enhance potency and durability of mRNA expression effectively.

Innovation Solution

Incorporating optimized 5′-UTR, coding region with a stop element, and 3′-UTR sequences, such as those similar to SEQ ID NOs:139-147, with modifications like miRNA binding sites, TENT recruiting sequences, and IDR/REDA sequences, to enhance mRNA stability and protein production.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If mRNA focuses on optimal ORF sequence design, then translation efficiency is improved, but potency and durability of mRNA expression are not sufficiently enhanced

Engineering Contradiction:

Improvetranslation efficiencyVSAvoidpotency and durability of expression

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent divides the mRNA molecule into distinct functional segments: optimized 5'-UTR for translation initiation, ORF for protein coding, stop element for termination, and optimized 3'-UTR for stability and localization. This segmentation allows each region to be independently optimized for its specific function, resolving the contradiction between translation efficiency and expression durability.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent applies local quality optimization by designing specific sequence characteristics for each mRNA region: the 5'-UTR contains specific secondary structures and motifs for ribosome binding, the 3'-UTR contains stability elements and polyadenylation signals, and the ORF is codon-optimized. Each region has tailored properties that enhance its specific function while contributing to overall expression potency and durability.

Inventive Principle:

Principle #3Local quality

2Duration of action of moving object

If mRNA half-life is extended through UTR optimization, then duration of action is improved, but sequence design complexity increases

Engineering Contradiction:

ImprovemRNA half-lifeVSAvoidsequence design complexity

Core Design Contradiction:

Duration of action of moving objectVSDevice complexity

Solution Approach 1:

The patent extends mRNA half-life by changing specific sequence parameters in the UTR regions: incorporating specific nucleotide compositions, secondary structures, and regulatory motifs in the 3'-UTR that enhance stability and protect against degradation. These parameter changes are targeted and controlled to achieve half-life extension without requiring complete redesign of the entire mRNA sequence.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250313830A1Messenger ribonucleic acids with extended half-life

Publication Date: 2025.10.09 MODERNATX INC

AI summary

The disclosure features a polynucleotide encoding a polypeptide, which polynucleotide comprises a 5′ UTR, a coding region encoding a polypeptide, and a 3 UTR, and lipid nanoparticles comprising the same. The polynucleotides and/or lipid nanoparticles of the present disclosure can increase the level and/or activity of the polypeptide by increasing the half-life and/or duration of expression of the polynucleotide encoding the polypeptide. Also disclosed herein are methods of treating a disease or disorder in a subject using the lipid nanoparticles of the present disclosure.