Double stranded oligonucleotides with stereochemical control
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Solution Overview
Problem
Current gene-targeting oligonucleotides face limitations due to susceptibility to nucleases, and there is a need for double-stranded oligonucleotides with improved properties for therapeutic, diagnostic, and research applications.
Innovation Solution
The development of double-stranded oligonucleotides with controlled structural elements, including chemical modifications and stereochemistry, such as phosphorothioate chiral centers and non-naturally occurring internucleotidic linkages, which enhance stability and activity, allowing for improved gene regulation and delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If naturally-occurring nucleic acids are used in gene-targeting applications, then the oligonucleotides can perform basic gene regulation functions, but they are susceptible to endo- and exo-nucleases which limits their stability and therapeutic utility
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleic acids through various modifications including phosphorothioate backbone modifications, 2'-O-methyl RNA modifications, and LNA (locked nucleic acid) modifications. These chemical parameter changes confer resistance to nucleases while maintaining gene silencing activity, directly resolving the contradiction between natural nucleic acid functionality and nuclease susceptibility
Solution Approach 2:
The patent employs composite materials by creating hybrid oligonucleotide structures that combine different modified nucleotide types within single molecules. For example, dsRNAi agents incorporate both 2'-O-methyl RNA modifications and phosphorothioate backbone modifications in specific patterns, creating composite structures that provide enhanced nuclease resistance while maintaining target specificity and biological activity
2Reliability
If chemical modifications are introduced to improve nuclease resistance, then stability increases, but the complexity of synthesis and manufacturing increases
Solution Approach 1:
The patent applies segmentation by dividing the oligonucleotide into regions with different modification patterns. For example, the 5' region may have one type of modification while the 3' region has another, allowing modular synthesis approaches and simplifying the overall manufacturing process while maintaining stability benefits
Solution Approach 2:
The patent implements local quality by placing specific chemical modifications at particular positions within the oligonucleotide sequence based on functional requirements. For instance, 2'-O-methyl modifications are placed in specific regions to enhance stability while phosphorothioate modifications are positioned to optimize nuclease resistance, allowing targeted optimization without uniformly complicating the entire molecule
3Productivity
If stereochemistry of backbone chiral centers is controlled to improve activity, then gene regulation efficacy increases, but the manufacturing precision requirements increase
Solution Approach 1:
The patent applies preliminary action by establishing the correct stereochemistry at backbone chiral centers during the synthesis process itself, rather than attempting to correct it afterward. The synthesis methods are designed to inherently produce the desired Rp or Sp configurations at phosphorothioate chiral centers, ensuring high activity while managing manufacturing precision requirements through process design rather than post-synthesis correction
Data Source
AI summary
The present disclosure provides double stranded oligonucleotides, compositions, and methods relating thereto. The present disclosure encompasses the recognition that structural elements of double stranded oligonucleotides, such as base sequence, chemical modifications (e.g, modifications of sugar, base, and/or internucleotidic linkages) or patterns thereof, 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, RNA interference (RNAi) activity, stability, delivery, etc. The present disclosure also provides methods for treatment of diseases using provided double stranded oligonucleotide compositions, for example, in RNA interference.