Synthetic mRNA UTR Composition for Stable Therapeutic Protein Expression
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The challenge lies in enhancing the stability, potency, and longevity of synthetic mRNA molecules for therapeutic applications, particularly in overcoming degradation by RNase enzymes and improving translation efficiency to produce active polypeptides or proteins effectively.
Innovation Solution
The development of heterologous mRNA constructs incorporating 5′ and 3′ UTR sequences from plant species, such as Arabidopsis thaliana, combined with a coding region to produce human proteins, and the use of chemically modified nucleotides to enhance translation efficiency and cytoplasmic half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If synthetic mRNA is used for therapeutic applications, then translational activity for producing polypeptides or proteins is achieved, but stability and longevity are reduced due to degradation by RNase enzymes
Solution Approach 1:
The patent applies parameter changes by chemically modifying the mRNA structure through 7-deazapurine nucleotides (isoguanine and isocytosine) to create 7-deaza nucleoside triphosphates. These chemical modifications change the physical and chemical parameters of the mRNA molecule, making it resistant to RNase degradation while preserving translational activity. The modified bases alter the molecular recognition sites that RNases typically target, thereby extending mRNA half-life in biological systems.
Solution Approach 2:
The invention creates a composite mRNA structure by incorporating non-natural 7-deaza nucleotides into the natural RNA backbone. This composite approach combines the translational functionality of natural mRNA with the enhanced stability of chemically modified nucleotides. The resulting hybrid molecule retains ribosome recognition and translation capability while gaining resistance to nucleolytic degradation, effectively merging the beneficial properties of both natural and modified components.
2Quantity of substance
If the level of therapeutic moiety in vivo is increased to improve drug success, then potency is enhanced, but the need for stability and longevity increases due to delivery and partitioning steps
Solution Approach 1:
By chemically modifying the mRNA with 7-deaza nucleotides, the patent changes the molecular parameters to resist enzymatic degradation. This allows the mRNA to maintain therapeutic protein production at elevated levels for extended periods in vivo, addressing both the need for high potency and extended duration of action without requiring continuous re-administration.
3Productivity
If translation efficiency is increased to produce more active polypeptide or protein, then potency is improved, but the complexity of molecular structure increases
Solution Approach 1:
The patent achieves enhanced translation efficiency through parameter changes in the nucleotide structure. The 7-deaza modification alters the electronic and steric properties of the base, which may improve ribosome binding affinity or translation elongation rates. This structural parameter change simultaneously boosts productivity while maintaining relative structural simplicity compared to more complex modification strategies.
Data Source
AI summary
This invention provides expressible polynucleotides, which can express a target protein or polypeptide. Synthetic mRNA constructs for producing a protein or polypeptide can contain one or more 5′ UTRs, where a 5′ UTR may be expressed by a gene of a plant. In some embodiments, a 5′ UTR may be expressed by a gene of a member of Arabidopsis genus. The synthetic mRNA constructs can be used as pharmaceutical agents for expressing a target protein or polypeptide in vivo.