mRNA Bioconjugates With Site-Specific Handles for Stable Delivery
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Solution Overview
Problem
Existing methods for modifying messenger RNA (mRNA) for therapeutic applications face challenges due to poor pharmacokinetic properties, rapid degradation, and difficulty in cellular delivery, with limited bioconjugation strategies that do not effectively address these issues.
Innovation Solution
Development of oligonucleotide bioconjugates and mRNA bioconjugates with specific chemical modifications, including alkyl and heteroatomic moieties, to enhance stability and cellular delivery, using methods such as reacting thiols with maleimides and succinimides to form covalent attachments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mRNA is used for therapeutic applications, then therapeutic efficacy is achieved, but pharmacokinetic properties are poor leading to rapid degradation and clearance
Solution Approach 1:
The patent applies composite materials by creating mRNA bioconjugates that combine mRNA with functional handle molecules. This composite structure allows the mRNA to maintain its therapeutic function while gaining improved pharmacokinetic properties through the attached functional handles that protect against degradation and enhance stability in vivo.
Solution Approach 2:
The patent uses functional handles as intermediaries between the mRNA and the biological environment. These functional handles serve as mediators that protect the mRNA from nucleases, prevent immune recognition, and facilitate controlled delivery, thereby improving pharmacokinetic stability without compromising therapeutic efficacy.
2Stability of the object's composition
If mRNA is modified with polymers or macromolecules to improve stability, then pharmacokinetic properties are enhanced, but site-specific covalent modification strategies are limited
Solution Approach 1:
The patent applies universality by developing a platform where functional handles can be attached to mRNA at specific sites and then used for diverse downstream applications. The same functional handle attachment strategy can be used for different therapeutic mRNAs and combined with various delivery systems, making the approach universally applicable across multiple contexts while maintaining stability.
Solution Approach 2:
The patent implements local quality by enabling site-specific covalent modification of mRNA at defined locations rather than random or global modification. This allows different functional handles to be attached at specific positions on the mRNA molecule, providing localized functional enhancement while preserving the overall mRNA structure and enabling versatile bioconjugation strategies.
3Adaptability or versatility
If internal bases of mRNA are modified, then functional groups can be added, but reactivity between purine and pyrimidine bases creates difficulty in site-specific modification
Solution Approach 1:
The patent applies local quality by introducing unique chemical handles at specific, predetermined positions within the mRNA sequence during synthesis. These localized handles have distinct chemical properties that allow for site-specific recognition and modification, enabling precise functional group addition at chosen locations without cross-reactivity with other bases.
Solution Approach 2:
The patent uses functional handles as intermediaries that are first incorporated at specific mRNA positions during synthesis, then serve as targeted attachment points for subsequent bioconjugation reactions. This two-step approach with the handle as an intermediary enables high site-specificity while maintaining the ability to add diverse functional groups.
4Ease of manufacture
If the 5' guanine cap is modified to enable bioconjugation, then covalent modification is easier, but translation efficiency is reduced
Solution Approach 1:
The patent applies local quality by placing functional handles and bioconjugation sites at positions away from the 5' cap region, specifically at internal or 3' positions on the mRNA. This localized modification approach enables easy covalent attachment of functional groups while preserving the integrity and function of the 5' cap for efficient translation initiation.
Solution Approach 2:
The patent extracts the bioconjugation function from the 5' cap region and places it at separate, non-cap locations on the mRNA molecule. By taking the modification capability out of the cap structure and positioning it elsewhere, the patent maintains both ease of manufacture for bioconjugation and high translation efficiency through preserved cap function.
Data Source
AI summary
The present disclosure relates to oligonucleotide bioconjugates for targeted therapy, and processes to make the same. The present disclosure also relates to mRNA bioconjugates and pharmaceutical formulations thereof which prevent, slow the progression, or reduce the severity of cancer. Additionally, the present disclosure relates to mRNA bioconjugates and pharmaceutical formulations thereof which prevent, slow the progression, or reduce the severity of obesity or one or more other metabolic and/or cardiovascular disorders.