Modified Antisense Oligonucleotides for Stable TGF-β2 Inhibition
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Solution Overview
Problem
Existing antisense oligonucleotides are ineffective in inhibiting TGF-β mRNA expression and lack stability, limiting their therapeutic potential for diseases related to overexpression of TGF-β proteins.
Innovation Solution
Development of novel antisense oligonucleotides with modified nucleosides, such as 2′-O-methoxyethyl (MOE)-modified nucleotides, to enhance TGF-β inhibitory effects and stability, including specific sequences like 5′-GGCGG CATGT CTATT TTGTA-3′, 5′-CGGCA TGTCT ATTTT GTAAA-3′, and 5′-GCGGC ATGTC TATTT TGTAA-3′.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense oligonucleotides are used, then they can bind to mRNA to form double chains, but they lack stability and have poor ability to inhibit TGF-β mRNA expression
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleosides within the oligonucleotide sequence. Specifically, it introduces modified nucleosides including 2′-O-methoxyethyl (MOE), 2′-fluoro (F), 2′-O-methyl (OMe), locked nucleic acid (LNA), ethylene-bridged nucleic acid (ENA), (R/S)-constrained ethyl (cET), and polyalkylene oxide (e.g., triethylene glycol (TEG)) modifications at the 2′ position of ribose pentose. These structural parameter changes enhance both the stability and inhibitory ability of the antisense oligonucleotide against TGF-β mRNA
Solution Approach 2:
The patent employs composite materials by creating hybrid oligonucleotide structures that combine modified nucleosides with standard nucleotides. The modified nucleosides are strategically positioned within the sequence (e.g., at 5′-end, 3′-end, or specific internal positions) to create a composite structure that leverages both the binding specificity of natural nucleotides and the enhanced stability and affinity properties of modified nucleosides, thereby resolving the contradiction between stability and inhibitory ability
2Reliability
If modified nucleosides are introduced to enhance TGF-β inhibitory effects, then stability improves, but molecular complexity increases
Solution Approach 1:
The patent applies local quality by introducing modifications at specific positions within the oligonucleotide sequence rather than uniformly throughout. The modified nucleosides are placed at strategic locations (5′-end, 3′-end, or specific internal positions) where they provide maximum benefit to stability and inhibitory ability while minimizing overall molecular complexity. This localized modification approach allows the molecule to maintain simplicity in non-critical regions while achieving enhanced performance at critical positions
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 antisense oligonucleotides demonstrate superior inhibition of TGF-β2 mRNA expression and improved stability, showing enhanced cancer cell killing effects and therapeutic potential for malignant tumors, benign tumors, immune diseases, and fibrosis.
Implementation Method 1
If there is a single strands of DNA or RNA having a sequence complementary to the mRNA in the course of this gene expression, this complementary DNA or RNA can bind to the mRNA to form a double chain, thereby blocking protein production.
Implementation Method 2
the nucleotide with the modified nucleoside may be a 2′-O-methoxyethyl (MOE)-modified nucleotide, a 2′-fluoro (F)-modified nucleotide, a 2′-O-methyl (0-Me)-modified nucleotide, a locked nucleic acid (LNA)-modified nucleotide
Data Source
AI summary
The present invention relates to novel antisense oligonucleotides including at least one modified nucleotide from among oligonucleotides of SEQ ID NOs: 1 to 3. The novel oligonucleotides exhibit an excellent effect of inhibiting the expression of TGF-β2 protein, an excellent effect of killing cancer cells, and improved stability in plasma. Therefore, the oligonucleotides of the present invention can be effectively used as a pharmaceutical composition for treating diseases related to TGF-β2 expression.