Antisense Oligonucleotide Inhibiting Chop Expression via LNA Modifications
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Solution Overview
Problem
Current methods lack an effective and efficient way to inhibit the expression of Chop, an intracellular mediator involved in various diseases, particularly those related to ER stress, as small molecules and antibodies are not suitable for targeting Chop due to its lack of enzymatic activity and intracellular location.
Innovation Solution
Development of an antisense oligonucleotide that hybridizes with the nucleic acid sequence of Chop mRNA and/or pre-mRNA, specifically designed to inhibit Chop expression by using modified nucleotides such as LNA, cET, or 2′Fluoro modified nucleotides, achieving significant reduction in Chop expression even at nanomolar concentrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If small molecules or antibodies are used to inhibit Chop, then the approach is simple, but they are not suitable for targeting Chop due to its lack of enzymatic activity and intracellular location
Solution Approach 1:
The patent employs antisense oligonucleotides as intermediary molecules that can penetrate cells and bind to Chop mRNA, thereby indirectly inhibiting Chop protein expression. This intermediary approach overcomes the limitation that small molecules and antibodies cannot effectively target intracellular non-enzymatic proteins like Chop.
2Device complexity
If conventional inhibition methods are used, then the device complexity is low, but they fail to achieve effective Chop inhibition
Solution Approach 1:
The patent modifies the chemical parameters of the oligonucleotide by incorporating locked nucleic acid (LNA) modifications, which enhance binding affinity and stability. This parameter change enables effective Chop inhibition at lower concentrations while maintaining reasonable molecular complexity.
3Reliability
If modified nucleotides such as LNA are used in the oligonucleotide, then the inhibition potency increases, but the manufacturing complexity increases
Solution Approach 1:
The patent applies LNA modifications at specific positions within the oligonucleotide sequence rather than uniformly throughout, optimizing binding affinity at critical regions while minimizing overall manufacturing complexity. This local quality approach balances potency enhancement with ease of production.
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 antisense oligonucleotide effectively inhibits Chop expression by up to 100% in various cell types, including cancer cells and immune cells, providing a potent tool for treating conditions associated with Chop imbalance, such as diabetes, cancer, and autoimmune disorders.
Implementation Method 1
an antisense oligonucleotide hybridizing with a nucleic acid sequence of C/EBP-homologous protein (Chop) mRNA and/or pre-mRNA
Data Source
AI summary
The present invention refers to an inhibitor consisting of oligonucleotides comprising 10 to 25 nucleotides, wherein at least one of the nucleotides is modified, and the oligonucleotide hybridizes with a nucleic acid sequence of C/EBP-homologous protein (Chop) of SEQ ID NO.1 (human) and/or SEQ ID NO. 48 (human) but also with mouse and rat sequences, wherein the oligonucleotide N inhibits at least 50% of the Chop expression. The invention is further directed to a pharmaceutical composition comprising such oligonucleotide.