RNA Editing Oligonucleotides for ADAR-Mediated USH2A Correction
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Solution Overview
Problem
Current treatments for Usher syndrome, particularly those targeting mutations in the USH2A gene, face limitations due to the size constraints of gene augmentation vectors and the need for specific exon skipping strategies, which do not address all pathogenic exons, leaving many patients without effective therapeutic options.
Innovation Solution
Development of RNA editing oligonucleotides (EONs) that form a complex with target RNA and utilize endogenous ADAR enzymes to deaminate specific adenosines in the USH2A pre-mRNA or mRNA, converting them to inosines to restore functional protein translation, particularly for mutations like c.11864G>A in exon 61.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gene augmentation therapy is used to treat Usher syndrome, then functional protein production can be restored, but the therapy is limited by vector cargo size constraints and cannot accommodate the large USH2A gene
Solution Approach 1:
The patent extracts only the critical functional domains of the usherin protein that are necessary for photoreceptor cell function, rather than attempting to deliver the entire USH2A gene. This selective extraction of essential functional elements allows gene augmentation therapy to overcome vector size limitations while still restoring sufficient protein function to treat the disease.
Solution Approach 2:
The patent segments the large USH2A gene into smaller, manageable functional domains that can be individually delivered via viral vectors. By dividing the gene into discrete functional units, the therapy can bypass cargo size constraints of current vector systems while still achieving restoration of protein function through coordinated expression of multiple segments.
2Reliability
If exon skipping strategies are used to treat Usher syndrome, then some pathogenic exons can be excluded from the mRNA, but this approach does not address all pathogenic exons and leaves many patients without effective treatment
Solution Approach 1:
The patent develops a universal therapeutic approach using antisense oligonucleotides that can target multiple different pathogenic exons across various USH2A mutations. This multi-functional design allows a single therapeutic platform to address diverse genetic variants, making the treatment adaptable to different patient genotypes rather than requiring mutation-specific therapies.
Solution Approach 2:
Instead of attempting to include all functional exons in the final protein product, the patent inverts the strategy by selectively excluding pathogenic exons through antisense-mediated repression. This negative selection approach reverses the conventional logic of gene therapy, achieving functional restoration by removing harmful elements rather than adding missing ones.
3Measurement precision
If antisense oligonucleotides are used to repress exon 61 translation, then the c.11864G>A mutation can be targeted, but the mechanism is not fully understood and may have off-target effects
Solution Approach 1:
The patent uses antisense oligonucleotides as intermediary molecules that bind to specific sequences in exon 61 pre-mRNA to block translation of the c.11864G>A mutation. These oligonucleotide intermediaries provide precise targeting through complementary base pairing while allowing reversible, controllable repression of the pathogenic transcript without permanently altering the genome.
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 EONs enable the correction of mutations in exons where exon skipping is not viable, potentially restoring functional usherin protein production and addressing unmet therapeutic needs for Usher syndrome.
Implementation Method 1
the EON when complexed with the target RNA molecule, and further complexed with an Adenosine Deaminase acting on RNA (ADAR), is capable of deaminating a target adenosine in the target RNA molecule
Data Source
AI summary
The invention relates to RNA editing oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA molecule in a eukaryotic cell, wherein said oligonucleotide is for use in the treatment of Usher syndrome, and more preferably for the deamination of target adenosines that are part of a premature stop codon present in the USH2A pre-mRNA or USH2A mRNA.