Antisense Oligonucleotides Modulating BDNF Expression
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Solution Overview
Problem
Current methods for modulating the expression and function of Brain-Derived Neurotrophic Factor (BDNF) are limited in their ability to specifically target and regulate BDNF polynucleotides, particularly in vivo or in vitro, with existing antisense oligonucleotides facing challenges in achieving significant and sustained modulation of BDNF mRNA levels.
Innovation Solution
The use of antisense oligonucleotides, specifically designed to have at least 50% sequence identity to a reverse complement of BDNF polynucleotides, administered via subcutaneous, intramuscular, or intravenous routes, which can target natural antisense transcripts to up-regulate or down-regulate BDNF expression, utilizing modified nucleotides such as phosphorothioate, LNA, and encapsulation in liposomes or carrier molecules to enhance delivery and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides are used to modulate BDNF expression, then BDNF mRNA levels can be increased or decreased, but the ability to achieve significant and sustained modulation is limited
Solution Approach 1:
The patent modifies the chemical parameters of oligonucleotides by incorporating phosphorothioate backbone modifications and LNA (locked nucleic acid) residues. These parameter changes enhance the stability, affinity, and sustained activity of the antisense oligonucleotides against BDNF mRNA, resolving the contradiction between achieving significant modulation and maintaining sustained effects.
Solution Approach 2:
The invention uses composite oligonucleotide structures combining different chemical components (phosphorothioate backbone, LNA residues, and DNA segments) to create enhanced antisense agents. This composite approach improves both the potency and duration of BDNF modulation, addressing the limitation of using conventional oligonucleotides alone.
2Reliability
If oligonucleotides are administered in vivo, then BDNF expression can be modulated in patient cells or tissues, but delivery and efficacy are challenging
Solution Approach 1:
The patent employs liposomes as intermediary delivery vehicles to transport the modified oligonucleotides to target tissues in vivo. This intermediary approach protects the oligonucleotides from degradation, enhances cellular uptake, and improves delivery efficiency to patient cells or tissues, resolving the contradiction between in vivo capability and delivery ease.
3Manufacturing precision
If antisense oligonucleotides target natural antisense transcripts to up-regulate BDNF, then a targeted approach is achieved, but specificity and precision in targeting are limited
Solution Approach 1:
The patent designs oligonucleotides with specific local modifications (phosphorothioate at particular positions, LNA residues at specific locations) to enhance binding affinity and specificity for natural antisense transcripts. This local quality approach allows precise targeting while maintaining the ability to adapt to different BDNF transcript variants, resolving the contradiction between targeting precision and flexibility.
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 or decreases BDNF mRNA levels in patient cells or tissues, as demonstrated by real-time PCR results, providing a targeted approach to modulate BDNF expression and function, potentially treating various neurological disorders.
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 Brain derived neurotrophic factor (BDNF), in particular, by targeting natural antisense polynucleotides of Brain derived neurotrophic factor (BDNF). The invention also relates to the identification of these antisense oligonecleotides and their use in treating diseases and disorders associated with the expression of BDNF.