Antisense Oligonucleotide Modulation of DMD Family Expression
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Solution Overview
Problem
Current methods for modulating the expression and function of DMD family polynucleotides, particularly in treating muscular dystrophy and related disorders, are limited in efficacy and specificity, as they often fail to effectively target and regulate the expression of dystrophin and associated proteins.
Innovation Solution
The use of antisense oligonucleotides, specifically designed to have at least 50% sequence identity to reverse complements of DMD family polynucleotides, which are administered to patient cells or tissues to modulate the expression and function of DMD family polynucleotides, either by up-regulating or down-regulating their activity, using phosphorothioate, locked nucleic acid (LNA), or other modified nucleotides, and can be delivered via liposomes or carrier molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional methods are used to modulate DMD family expression, then treatment simplicity is maintained, but efficacy and specificity are insufficient
Solution Approach 1:
The patent modifies the chemical structure of oligonucleotides by incorporating phosphorothioate linkages and locked nucleic acid (LNA) modifications. These parameter changes in the molecular structure enhance the oligonucleotides' ability to bind to target DMD family mRNA, thereby improving treatment efficacy and specificity while maintaining reasonable method complexity through standardized synthesis protocols.
2Measurement precision
If antisense oligonucleotides are designed with high sequence identity to reverse complements, then specificity targeting is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies local modifications at specific positions within the oligonucleotide sequence, particularly incorporating phosphorothioate linkages at specific internucleotide positions and LNA modifications at predetermined locations. This localized modification approach enhances binding specificity to the DMD family target while avoiding the need to redesign the entire oligonucleotide structure, thus maintaining manufacturability through targeted rather than comprehensive modifications.
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
This approach significantly increases the expression of DMD family mRNA levels, as demonstrated by real-time PCR results, providing a therapeutic means to treat muscular dystrophy and related disorders by specifically targeting and modulating the expression of dystrophin and associated proteins.
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
Implementation Method 2
Antisense DNA has the added feature that DNA-RNA hybrids serve as a substrate for digestion by ribonuclease H, an activity that is present in most cell types
Data Source
AI summary
The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Dystrophin family, in particular, by targeting natural antisense polynucleotides of Dystrophin family. The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of DMD family.