Allele-Specific Antisense Oligonucleotides for Mutant COCH Silencing
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Solution Overview
Problem
Current treatments for dominantly inherited progressive hearing loss and vestibular dysfunction caused by DFNA9, such as gene augmentation therapy, are ineffective as they do not address the formation of cytotoxic cochlin dimers and unprocessed cochlin proteins, and there is a need for targeted therapy to prevent mutant cochlin production.
Innovation Solution
Development of allele-specific antisense oligonucleotides that specifically degrade mutated COCH transcripts, targeting sequences with high complementarity and minimal mismatches to avoid immunogenicity and ensure efficient degradation of mutant mRNA while preserving wildtype protein production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gene augmentation therapy is used to treat DFNA9, then the patient receives a therapeutic intervention, but the therapy is ineffective because it does not address the formation of cytotoxic cochlin dimers and unprocessed cochlin proteins
Solution Approach 1:
The patent extracts and removes the harmful mutated COCH transcript from the system using antisense oligonucleotides that specifically bind to and degrade only the mutant mRNA, leaving the wild-type gene intact. This extraction approach directly eliminates the source of cytotoxic cochlin dimers without affecting normal protein production.
Solution Approach 2:
The patent changes the molecular parameters of the COCH transcript by introducing complementary antisense sequences that induce conformational changes and recruitment of RNase H1, leading to selective degradation of the mutant transcript. This parameter change enables specific targeting based on sequence differences between mutant and wild-type alleles.
2Productivity
If antisense oligonucleotides are designed to bind to mutated COCH transcripts, then specific degradation of mutant mRNA is achieved, but the design must maintain high complementarity to avoid immunogenicity while ensuring efficient degradation
Solution Approach 1:
The patent applies local quality by designing antisense oligonucleotides with high complementarity specifically at the mutation site and flanking regions, while maintaining moderate complementarity elsewhere. This localized high-affinity binding ensures efficient degradation of mutant transcripts while minimizing off-target effects and immunogenic responses.
Solution Approach 2:
The patent creates a complementary copy of the mutant COCH transcript sequence that is sufficiently similar to bind specifically to the target mRNA but contains deliberate mismatches or modifications that prevent recognition by the immune system while maintaining degradation capability through RNase H1 recruitment.
3Reliability
If allele-specific antisense oligonucleotides are used to degrade mutated COCH transcripts, then mutant cochlin production is prevented, but the therapy must specifically distinguish between mutant and wildtype alleles to preserve functional cochlin proteins
Solution Approach 1:
The patent performs preliminary action by designing antisense oligonucleotides that pre-target and bind to specific mutant allele sequences before translation occurs, preventing the formation of harmful proteins. The oligonucleotides are designed with sequences that exploit known mutant-specific variations (such as the c.151C>T or c.263G>A founder mutations) to achieve allele-specific degradation.
Solution Approach 2:
The patent applies inversion by using the sequence differences between mutant and wild-type alleles in reverse - instead of trying to protect the wild-type allele, the therapy specifically targets and degrades the mutant allele by designing antisense sequences that are complementary only to the mutant variant, thereby inverting the selective pressure to work against the harmful allele.
4Duration of action of stationary object
If the therapy targets the COCH gene to prevent cytotoxic dimer formation, then disease progression is delayed, but the treatment must be applied continuously to maintain sufficient functional cochlin protein levels
Solution Approach 1:
The patent implements continuous useful action by establishing sustained antisense oligonucleotide presence in the target tissue through repeated administrations or sustained-release formulations. This continuous action ensures ongoing degradation of mutant transcripts and maintains adequate levels of functional cochlin protein throughout the treatment period, delaying disease progression.
Solution Approach 2:
The patent applies beforehand cushioning by maintaining a reservoir of functional cochlin protein through continuous low-level suppression of mutant allele expression, preventing the accumulation of cytotoxic dimers before they can cause significant damage. This proactive approach cushions against disease progression rather than reacting to established damage.
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 antisense oligonucleotides effectively prevent the formation of cytotoxic cochlin dimers, delaying disease progression and improving the quality of life for patients by reducing hearing loss and balance issues.
Implementation Method 1
an antisense oligonucleotide for the specific degradation of a mutated COCH transcript that binds to and/or is complementary to a polynucleotide with the nucleotide sequence as set forward in SEQ ID NO: 1 or in SEQ ID NO: 2
Implementation Method 2
DNA-based antisense oligonucleotides containing thymine residues instead of uracil residues, have been shown to effectively target (pre)mRNA molecules for degradation by the RNase H1 enzyme
Data Source
AI summary
The invention relates to the fields of medicine and immunology. In particular, it relates to novel antisense oligonucleotides that may be used in the treatment, prevention and/or delay of an COCH associated condition.