Antisense Oligonucleotide Modulation of SIRT Expression via Chemical Modifications
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Solution Overview
Problem
Current methods for modulating Sirtuin (SIRT) expression and function in cells are limited in specificity and efficacy, particularly in using antisense oligonucleotides that target specific sequences to regulate SIRT activity for therapeutic applications.
Innovation Solution
The use of antisense oligonucleotides, specifically designed to have at least 50% sequence identity to reverse complements of SIRT polynucleotides, administered via subcutaneous, intramuscular, intravenous, or intraperitoneal routes, to modulate SIRT expression and function by binding to sense and antisense SIRT polynucleotides, utilizing modified nucleotides and bonds such as phosphorothioate, LNA, and 2′-O-methyl modifications, and encapsulated in liposomes or attached to carriers like cholesterol or TAT peptide.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides are used to modulate SIRT expression, then SIRT activity can be regulated for therapeutic applications, but specificity and efficacy are limited
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of oligonucleotides through phosphorothioate backbone modifications and LNA (locked nucleic acid) incorporations. These chemical parameter changes enhance both the binding affinity (specificity) and stability (efficacy) of the antisense oligonucleotides against SIRT mRNA, resolving the contradiction between therapeutic efficacy and sequence specificity.
Solution Approach 2:
The invention uses composite materials by combining different oligonucleotide components: phosphorothioate-modified DNA backbone with LNA-containing RNA segments. This composite structure integrates the stability and nuclease resistance of phosphorothioate DNA with the high binding affinity of LNA RNA, achieving both improved specificity and therapeutic efficacy simultaneously.
2Ease of operation
If oligonucleotides are administered via injection routes, then delivery into cells is achieved, but sustained effects over time are limited
Solution Approach 1:
The patent employs partial action by using a moderate oligonucleotide length (15-30 nucleotides) with optimized phosphorothioate modification ratios. This partial modification approach balances cellular uptake efficiency with prolonged circulation half-life, achieving sustained therapeutic effects without requiring excessive chemical modifications that might impair delivery.
Solution Approach 2:
The invention achieves continuity of useful action through the stable phosphorothioate backbone that resists nuclease degradation in vivo. This continuous protection allows the oligonucleotide to maintain its binding activity against SIRT mRNA over extended periods (48-72 hours), providing sustained therapeutic effect following a single administration.
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
Significantly increases SIRT1 mRNA levels in cells, demonstrating effective modulation of SIRT expression and function, as shown in experiments with HepG2 cells and monkey fat biopsies, with sustained effects over 48 hours, enhancing therapeutic potential for various diseases.
Implementation Method 1
DNA-RNA and RNA-RNA hybridization are important to many aspects of nucleic acid function including DNA replication, transcription, and translation. Hybridization is also central to a variety of technologies that either detect a particular nucleic acid or alter its expression. Antisense nucleotides, for example, disrupt gene expression by hybridizing to target RNA
Data Source
AI summary
The present invention relates to antisense oligonucleotide that modulate the expression of and/or function of a Sirtuin (SIRT), in particular, by targeting natural antisense polynucleotides of a Sirtuin (SIRT). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of Sirtuins (SIRT)s.