2'-O-N-alkyl acetamide modified oligonucleotides for CNS splicing modulation
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Solution Overview
Problem
Current methods for modulating transcript processing, such as antisense oligonucleotides, face limitations in effectively addressing aberrant splicing caused by point mutations, which can lead to genetic diseases, particularly in terms of cellular uptake and pharmacologic activity in muscle tissue and the central nervous system.
Innovation Solution
Development of oligomeric compounds with 2′-O—(N-alkyl acetamide) modified sugar moieties, which enhance cellular uptake and pharmacologic activity, specifically designed to modulate splicing of pre-mRNA in muscle tissue and the central nervous system, by targeting specific splice sites and processing sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense oligonucleotides are used to target aberrant splice sites, then splicing modulation capability is achieved, but cellular uptake and pharmacologic activity in muscle tissue and CNS are insufficient
Solution Approach 1:
The patent modifies the sugar moiety of the oligonucleotide from conventional 2′-deoxyribose to 2′-O—(N-alkyl acetamide) modified sugar, changing the chemical parameters of the molecule to improve cellular uptake and pharmacologic activity while maintaining splicing modulation capability
Solution Approach 2:
The patent creates a composite oligonucleotide structure combining modified sugar moieties (2′-O—(N-alkyl acetamide)) with conventional nucleobases and phosphate backbones, resulting in a hybrid molecule that retains target specificity while gaining improved cellular penetration and pharmacologic properties
2Measurement precision
If conventional oligonucleotide structures are used, then sequence specificity for targeting mutations is maintained, but pharmacologic activity in muscle tissue and central nervous system is limited
Solution Approach 1:
The patent changes the sugar moiety parameters (from 2′-deoxyribose to 2′-O—(N-alkyl acetamide) modified sugar) to enhance pharmacologic activity and tissue penetration while preserving the nucleobase sequence that provides target specificity
3Productivity
If standard antisense compounds are administered, then some splicing modulation is achieved, but the ability to effectively address aberrant splicing in genetic diseases is insufficient
Solution Approach 1:
The patent modifies chemical parameters of the oligonucleotide (sugar moiety structure) to enhance cellular uptake and pharmacologic activity, thereby improving the efficiency of splicing modulation and the ability to correct aberrant splicing in genetic diseases
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 modified oligonucleotides demonstrate improved ability to modulate splicing processes, including enhanced cellular uptake and pharmacologic activity, effectively addressing aberrant splicing and related genetic diseases by targeting specific sites within the pre-mRNA.
Implementation Method 1
The sequence specificity of antisense compounds makes them extremely attractive as tools for target validation and gene functionalization
Data Source
AI summary
Provided herein are methods, compounds, and compositions for modulation of transcript processing.