Gapmer Antisense Oligonucleotides Reducing Hepatotoxicity
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Solution Overview
Problem
Current antisense compounds for disease-causing gene inhibition face challenges with toxicity and cost, particularly with high-affinity methyleneoxy (4′-CH2—O-2′) bicyclic nucleic acid (BNA) moieties, which, despite potency, increase hepatotoxicity risks.
Innovation Solution
Development of gapmer antisense oligonucleotides incorporating non-bicyclic high-affinity modified nucleotides, such as 2′-modified nucleosides, to reduce toxicity while maintaining or enhancing efficacy, featuring a deoxy gap region with 5′ and 3′ wing regions containing bicyclic and non-bicyclic nucleotides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high-affinity methyleneoxy (4'-CH2-O-2') bicyclic nucleic acid (BNA) moieties are used to create potent gapmer antisense oligonucleotides, then antisense activity and potency are improved, but hepatotoxicity increases as indicated by elevation of liver transaminases in rodent experiments
Solution Approach 1:
The patent applies local quality by replacing only a portion of the BNA/LNA nucleotides with non-bicyclic high-affinity modified nucleotides in the wing regions, while retaining some bicyclic nucleotides. This creates a heterogeneous structure where different nucleotide types are localized to specific positions, achieving reduced hepatotoxicity while maintaining sufficient binding affinity to the target RNA.
Solution Approach 2:
The patent creates composite antisense oligonucleotides by combining multiple types of nucleotides: bicyclic nucleic acid (BNA/LNA) nucleotides, non-bicyclic high-affinity modified nucleotides, and potentially other modified nucleotides. This composite approach allows the molecule to exhibit both high target affinity (from the bicyclic and modified nucleotides) and reduced toxicity (from the non-bicyclic components).
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 proposed gapmer antisense oligonucleotides demonstrate improved safety and efficacy compared to previous BNA or LNA compounds, reducing toxicity and maintaining or increasing potency, thus offering a more effective therapeutic option.
Implementation Method 1
the principle behind antisense technology is that an antisense compound hybridizes to a target nucleic acid and effects modulation of gene expression activity or function
Implementation Method 2
An example of modulation of RNA target function by degradation is RNase H-based degradation of the target RNA upon hybridization with a DNA-like antisense compound
Data Source
AI summary
Provided herein are gapmer oligomeric compounds for reduction of target RNA in vivo comprising different nucleotide modifications within one or both wing regions. Also provided are methods of using such oligomeric compounds, including use in animals. In certain embodiments, such compound have desirable potency and toxicity characteristics.