Antisense Oligonucleotides Targeting ATOH1 Natural Antisense Transcripts
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Solution Overview
Problem
Current methods for modulating the expression and function of ATOH1 polynucleotides are limited in their ability to specifically target and regulate the natural antisense transcripts, leading to incomplete or inefficient modulation of gene expression.
Innovation Solution
The use of antisense oligonucleotides, specifically designed to have at least 50% sequence identity to a reverse complement of ATOH1 polynucleotides, which are administered to patient cells or tissues to up-regulate or down-regulate the expression of ATOH1, utilizing modified nucleotides and delivery methods such as liposomes or carrier molecules for enhanced efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If antisense oligonucleotides are designed to target natural antisense transcripts of ATOH1, then the specificity and effectiveness of gene expression modulation is improved, but the complexity of the treatment approach increases
Solution Approach 1:
The patent uses antisense oligonucleotides as intermediary molecules that bind to natural antisense transcripts of ATOH1, forming DNA-RNA hybrids that serve as substrates for ribonuclease H digestion. This intermediary approach allows indirect modulation of ATOH1 expression by targeting the antisense transcript rather than the sense transcript directly, thereby improving specificity while managing complexity through a well-defined molecular mechanism
Solution Approach 2:
The patent employs chemical modifications of the oligonucleotide backbone (such as phosphorothioate modifications) to change the physical and chemical parameters of the antisense molecule. These parameter changes enhance the stability, binding affinity, and resistance to nucleases of the oligonucleotides, thereby improving the effectiveness of gene expression modulation while allowing for optimized treatment protocols
2Reliability
If oligonucleotides are used to inhibit natural antisense transcripts, then the modulation of ATOH1 expression is enhanced, but the delivery efficiency and cellular uptake remain challenging
Solution Approach 1:
The patent employs delivery vehicles such as liposomes or carrier molecules as intermediaries to facilitate the cellular uptake of antisense oligonucleotides. These delivery systems act as mediators that protect the oligonucleotides from degradation in the extracellular environment and enhance their penetration into target cells, thereby improving delivery efficiency without compromising the modulation reliability
Solution Approach 2:
The patent uses composite structures combining oligonucleotides with delivery vehicles (such as liposome-oligonucleotide complexes). This composite approach integrates the therapeutic oligonucleotide with delivery-enhancing materials, thereby simultaneously achieving reliable gene expression modulation and improved cellular uptake through the synergistic properties of the composite system
3Reliability
If antisense oligonucleotides are administered to up-regulate ATOH1 expression, then therapeutic benefit is achieved, but potential off-target effects and toxicity increase
Solution Approach 1:
The patent designs oligonucleotides with high sequence specificity that target only the natural antisense transcripts of ATOH1. By optimizing the sequence complementarity and binding specificity, the treatment achieves localized and precise modulation of ATOH1 expression in target tissues, thereby minimizing off-target effects and reducing potential toxicity while maintaining therapeutic benefit
Solution Approach 2:
The patent uses ribonuclease H as a natural cellular intermediary to degrade the DNA-RNA hybrids formed by the antisense oligonucleotides. This enzymatic mechanism provides a built-in safety feature that limits the duration and extent of oligonucleotide action, thereby reducing the risk of prolonged off-target effects and toxicity while maintaining effective therapeutic modulation of ATOH1 expression
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 effectively modulates the expression and function of ATOH1 polynucleotides, as demonstrated by increased ATOH1 mRNA levels in treated cells, offering a targeted therapeutic option for related diseases and 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. 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
Figure 1
AI summary
The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Atonal homolog 1 (ATOH1), in particular, by targeting natural antisense polynucleotides of Atonal homolog 1 (ATOH1). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of ATOH1.