Modified Antisense Oligonucleotides for SNP-Specific Target Binding
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Solution Overview
Problem
Existing antisense compounds lack specificity and efficiency in modulating target nucleic acids, particularly in the context of single-nucleotide polymorphisms associated with various diseases, and there is a need for improved oligonucleotides that can effectively target specific nucleobase sequences.
Innovation Solution
The development of chemically modified oligonucleotides with specific nucleobase sequences that differ by 1-3 nucleobases from target nucleic acids, featuring modified nucleosides in the 5′- and 3′-regions and a central region with varying numbers of modified and unmodified deoxynucleosides, enhancing binding specificity and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional antisense compounds are used, then general binding to target nucleic acids is achieved, but specificity and efficiency in modulating target nucleic acids with single-nucleotide polymorphisms is insufficient
Solution Approach 1:
The patent applies local quality by introducing chemically modified nucleosides at specific local positions within the oligonucleotide sequence. The 5′- and 3′-regions contain modified nucleosides that provide enhanced binding specificity to target nucleic acids with single-nucleotide polymorphisms, while the central region maintains standard nucleosides for structural stability. This localized modification strategy enables the compound to distinguish between target and non-target sequences with high precision.
Solution Approach 2:
The patent employs parameter changes by systematically varying the chemical modifications in the 5′- and 3′-regions to optimize binding characteristics. Different chemically modified nucleosides are used at specific positions to adjust the affinity and specificity parameters of the oligonucleotide-tDNA complex, enabling effective modulation of target nucleic acids while minimizing off-target effects.
2Measurement precision
If oligonucleotides with modified nucleosides in 5′- and 3′-regions are designed, then binding specificity to target nucleic acids is improved, but structural complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the oligonucleotide into three distinct functional regions: a 5′-region with chemically modified nucleosides for initiating specific binding, a central region with standard nucleosides providing structural stability, and a 3′-region with modified nucleosides for maintaining specificity. This segmented architecture allows each region to perform its specific function while keeping the overall structure manageable and synthesizable.
Solution Approach 2:
The patent implements local quality by concentrating chemical modifications only in the 5′- and 3′-regions rather than throughout the entire oligonucleotide. This localized approach enhances binding specificity where needed while avoiding the excessive structural complexity that would result from modifying all nucleosides uniformly.
3Reliability
If chemically modified nucleosides are used in the oligonucleotide, then efficacy in modulating target nucleic acids is enhanced, but manufacturing complexity increases
Solution Approach 1:
The patent applies local quality by limiting chemical modifications to specific 5′- and 3′-regions, which simplifies the synthesis process compared to modifying all nucleosides. The central region uses standard, easily synthesized nucleosides, while only the terminal regions require specialized chemical modifications, thereby maintaining high efficacy while reducing manufacturing complexity.
Solution Approach 2:
The patent segments the oligonucleotide into regions with different modification requirements, allowing standard synthesis methods to be used for the central region while applying specialized chemistry only where necessary. This segmentation strategy makes the overall manufacturing process more manageable and scalable.
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
These modified oligonucleotides demonstrate improved target specificity and efficacy in modulating target nucleic acids, particularly in the context of single-nucleotide polymorphisms associated with diseases, offering potential therapeutic applications.
Implementation Method 1
the modified oligonucleotide has a nucleobase sequence complementary to the nucleobase sequence of a target region of a target nucleic acid
Data Source
AI summary
The present invention provides oligomeric compounds. 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 activity or expression of the target nucleic acid in a cell.