Antisense Oligonucleotides Modulating Usher Transcript Splicing
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Solution Overview
Problem
Current treatments for Usher Syndrome, a genetic cause of combined blindness and deafness, are inadequate in effectively addressing the underlying genetic mutations that lead to cryptic splicing in the Usher transcript, resulting in improper protein expression and cellular dysfunction.
Innovation Solution
Development of modified oligonucleotides that are complementary to specific regions of the Usher transcript, including exon 2, intron 2, exon 3, and intron 3, to inhibit cryptic splicing and promote normal splicing, thereby correcting protein expression by targeting and modulating the splicing of the Usher transcript.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for Usher Syndrome, then general symptom management is provided, but the underlying genetic mutations and cryptic splicing are not effectively addressed
Solution Approach 1:
The patent uses antisense oligonucleotides as intermediary molecules that bind to the cryptic splice site sequences on the Usher transcript, preventing the splicing machinery from recognizing and utilizing these abnormal splice sites. This intermediary approach blocks the harmful cryptic splicing without directly altering the genetic mutation itself.
Solution Approach 2:
The invention extracts or removes the problematic cryptic splice site sequences from the splicing pathway by using complementary oligonucleotides that selectively bind to and sequester these abnormal sequences, preventing them from being incorporated into the mature mRNA transcript.
2Reliability
If antisense compounds are designed to bind to Usher transcript, then cryptic splicing is inhibited, but specificity and off-target effects must be managed
Solution Approach 1:
The patent designs oligonucleotides with highly specific local complementarity to unique sequences within the cryptic splice sites of the Usher transcript. By targeting specific local regions with precise sequence matching, the invention achieves selective binding that minimizes off-target effects while maximizing splicing correction at the intended site.
Solution Approach 2:
The invention replaces non-specific chemical interactions with sequence-specific hybridization mechanics. The oligonucleotides use Watson-Crick base pairing rules to achieve specific recognition and binding only to complementary sequences, providing high specificity through molecular recognition rather than random chemical affinity.
3Productivity
If modified oligonucleotides are used to target cryptic splice sites, then normal splicing is increased, but delivery and stability challenges arise
Solution Approach 1:
The patent employs chemically modified oligonucleotides with altered sugar moieties (such as 2′-O-methyl, 2′-O-methoxyethyl) and backbone structures (such as phosphorothioates) to enhance nuclease resistance, improve cellular uptake, and increase plasma stability. These parameter changes in chemical structure address delivery and stability challenges while maintaining sequence-specific binding capability.
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 modified oligonucleotides effectively inhibit cryptic splicing, increasing normal splicing and correcting protein expression, which can lead to improved cellular function and potentially ameliorate symptoms of Usher Syndrome such as deafness and blindness.
Implementation Method 1
oligonucleotides are complementary to an Usher transcript... oligonucleotides inhibit cryptic splicing... normal splicing is increased
Data Source
AI summary
The present invention provides compounds comprising oligonucleotides complementary to an Usher transcript. Certain such compounds are useful for hybridizing to an Usher transcript, including but not limited, to an Usher transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the Usher transcript. In certain such embodiments, the Usher transcript includes a mutation that results in cryptic splicing and hybridization of the oligonucleotide results in a decrease in the amount of cryptic splicing. In certain embodiments, such compounds are used to treat Usher Syndrome.