Oligonucleotide Structural Control for Stability and Delivery
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Solution Overview
Problem
Existing oligonucleotides lack control over structural elements such as base sequence, chemical modifications, and stereochemistry, which affects their stability, toxicity, delivery, and specificity in therapeutic, diagnostic, and research applications.
Innovation Solution
Development of oligonucleotides with controlled structural elements, including specific patterns of sugar modifications, base modifications, and backbone stereochemistry, to enhance their activities and properties such as stability, specificity, and delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligonucleotides use natural structures without controlled modifications, then they are easier to manufacture and less complex, but they exhibit reduced stability, specificity, and delivery efficiency
Solution Approach 1:
The patent applies local quality by introducing specific chemical modifications at particular positions within the oligonucleotide structure. Different sugar modifications (2'-OMe, 2'-F, 2'-MOE) are placed at specific positions to enhance stability and specificity without modifying the entire structure uniformly. This localized modification approach improves reliability while maintaining manageable complexity.
Solution Approach 2:
The patent employs asymmetry by creating non-uniform patterns of chemical modifications along the oligonucleotide backbone. The modifications are distributed in asymmetric patterns rather than uniform repetition, which enhances the three-dimensional structure and interaction with target molecules, thereby improving stability and specificity while adding controlled structural complexity.
2Manufacturing precision
If oligonucleotides incorporate multiple chemical modifications and stereochemical controls, then they achieve improved specificity and stability, but they become more difficult to manufacture with reduced productivity
Solution Approach 1:
The patent applies segmentation by dividing the oligonucleotide synthesis into modular components with standardized modification patterns. By creating repeatable structural modules with defined sugar modifications and stereochemistry, the manufacturing process can be standardized and scaled, improving manufacturing precision while maintaining productivity through modular assembly approaches.
Solution Approach 2:
The patent utilizes parameter changes by systematically varying specific chemical parameters (types of sugar modifications, positions of modifications, stereochemical configurations) to optimize structural control. This systematic parameter optimization enables precise manufacturing control while streamlining the development process for improved productivity.
3Stability of the object's composition
If oligonucleotides use modified sugar moieties and backbone structures, then they achieve enhanced delivery and stability, but they increase the complexity of the molecular structure
Solution Approach 1:
The patent applies preliminary action by pre-establishing optimized patterns of sugar modifications and backbone structures during the design phase. These pre-configured structural elements are incorporated into the oligonucleotide sequence to ensure enhanced stability and delivery from the outset, rather than attempting to achieve these properties through post-synthesis modifications.
Solution Approach 2:
The patent employs composite materials by combining different types of sugar modifications (2'-OMe, 2'-F, 2'-MOE) with various backbone structures in a single oligonucleotide molecule. This composite approach creates a hybrid structure that leverages the beneficial properties of each modification type to achieve enhanced stability and delivery while distributing the molecular complexity across multiple functional components.
Data Source
AI summary
Among other things, the present disclosure provides oligonucleotides, compositions, and methods thereof. Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages) or patterns thereof, conjugation with additional chemical moieties, and/or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages)], and/or patterns thereof, can have significant impact on oligonucleotide properties and activities, e.g., knockdown ability, stability, delivery, etc. In some embodiments, the oligonucleotides decrease the expression, activity and/or level of a C9orf72 gene, including but not limited to, one comprising a repeat expansion, or a gene product thereof. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions, for example, in treatment of C9orf72-related disorders.