Modified Linkages in Gapped Oligomeric Compounds for RNA Selectivity
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Solution Overview
Problem
Existing antisense compounds face challenges in achieving selective targeting of specific RNA sequences while minimizing off-target effects and improving stability and therapeutic index.
Innovation Solution
The development of gapped oligomeric compounds with modified internucleoside linkages, such as formulas I to XVI, which enhance selectivity for target RNA and improve stability, allowing for more effective hybridization and modulation of gene expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemically modified nucleosides are incorporated into antisense compounds to enhance nuclease resistance and pharmacokinetics, then stability and efficacy are improved, but compound complexity and manufacturing difficulty increase
Solution Approach 1:
The oligonucleotide is divided into distinct functional regions: a gapmer region with modified nucleosides for RNase H recruitment and stability, and flanking regions with different modifications for affinity and pharmacokinetics. This segmentation allows optimization of each region's properties independently while managing overall compound complexity.
Solution Approach 2:
The compound combines multiple types of chemically modified nucleosides (2'-O-methoxyethyl, bicyclic sugars like LNA or cEt, phosphorothioate linkages) within a single oligonucleotide structure. This composite approach integrates diverse chemical modifications that collectively enhance nuclease resistance, stability, and efficacy while maintaining manageable complexity through systematic design.
2Reliability
If higher doses of antisense compounds are administered to achieve therapeutic effects, then potency is improved, but toxicity increases
Solution Approach 1:
Different regions of the oligonucleotide are assigned different chemical modifications optimized for specific functions: the gapmer region uses 2'-deoxy nucleosides for RNase H recruitment, while flanking regions use 2'-O-methoxyethyl or bicyclic modifications for enhanced affinity and pharmacokinetics. This local optimization improves potency at lower doses by ensuring each region contributes maximally to its intended function, thereby reducing the required dose and associated toxicity.
Solution Approach 2:
The compound employs phosphorothioate internucleoside linkages in specific regions to enhance serum stability and nuclease resistance, allowing the compound to maintain efficacy at lower doses with reduced clearance. This parameter change in chemical stability directly impacts dosing requirements and toxicity profile by extending half-life and reducing the frequency and total dose required.
3Adaptability or versatility
If antisense compounds are designed for broad target coverage, then versatility is improved, but selectivity for specific RNA sequences decreases
Solution Approach 1:
The oligonucleotide design incorporates a central gapmer region flanked by regions with different chemical modifications. The flanking regions with 2'-O-methoxyethyl or bicyclic nucleosides provide enhanced binding affinity and selectivity for specific target sequences, while the gapmer region maintains versatility for RNase H recruitment. This local differentiation allows the compound to achieve both high selectivity for the intended target and broad applicability across different disease targets.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The gapped oligomeric compounds provide improved selectivity and toxicity profile, enhancing the therapeutic index and stability during synthesis, thereby facilitating more efficient modulation of target nucleic acid activity.
Implementation Method 1
the gapped oligomeric compounds provide improved selectivity and toxicity profile, enhancing the therapeutic index and stability during synthesis, thereby facilitating more efficient modulation of target nucleic acid activity
Implementation Method 2
The development of gapped oligomeric compounds with modified internucleoside linkages, such as formulas I to XVI, which enhance selectivity for target RNA and improve stability
Data Source
AI summary
The present invention provides gapped oligomeric compounds comprising from 1 to about 3 internucleoside linkages having one of formulas I to XVI. In certain embodiments, inclusion of from 1 to about 3 internucleoside linkages of one of formulas I to XVI, improves selectivity for a target RNA relative to an off target RNA. In certain embodiments, the improved selectivity also provides an improved toxicity profile. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount of activity or expression of the target nucleic acid in a cell.