USH2A Oligonucleotides Exon 13 Skipping
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Solution Overview
Problem
Current treatments for Usher Syndrome Type 2A and other conditions associated with mutations in the USH2A gene, such as retinitis pigmentosa, are limited in their ability to effectively restore usherin protein activity and improve vision.
Innovation Solution
Development of USH2A oligonucleotides capable of mediating the skipping of deleterious exons, specifically exon 13, in USH2A gene transcripts, leading to the production of internally truncated but partially functional usherin protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for Usher Syndrome Type 2A, then current treatment limitations are maintained, but the ability to restore usherin protein activity and improve vision remains insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of oligonucleotides, specifically controlling the stereochemistry of phosphorothioate linkages (Rp or Sp configuration) and incorporating various sugar and base modifications. These parameter changes in the oligonucleotide structure enable efficient exon 13 skipping while maintaining high stability and low toxicity, thereby restoring usherin protein activity and improving vision efficacy
2Reliability
If oligonucleotides are designed to skip exon 13 in USH2A transcripts, then partially functional usherin protein is produced, but the complexity of oligonucleotide structure increases
Solution Approach 1:
The patent applies local quality by making specific modifications at particular positions within the oligonucleotide structure. Different sugar modifications (2'-O-methyl, 2'-fluoro, 2'-deoxy), base modifications (5-methylcytosine, inosine), and linkage modifications (phosphorothioate with controlled Rp/Sp stereochemistry) are strategically placed at specific positions to optimize exon skipping efficiency, stability, and selectivity while managing structural complexity
3Productivity
If high concentrations of oligonucleotides are used to achieve exon skipping, then skipping efficiency increases, but toxicity may increase
Solution Approach 1:
The patent reduces oligonucleotide toxicity while maintaining high exon skipping efficiency through parameter changes in chemical structure. Specifically, controlled stereochemistry of phosphorothioate linkages (enantiopure or enriched Rp or Sp configuration) and strategic sugar modifications enhance stability and reduce immunogenicity, allowing effective exon skipping at lower concentrations with reduced toxicity
Solution Approach 2:
The patent employs composite materials by combining multiple modified nucleotide components within a single oligonucleotide structure. The oligonucleotide comprises a mixture of nucleotides with different modifications (2'-O-methyl, 2'-fluoro, phosphorothioate linkages, base modifications) in specific ratios, creating a composite structure that optimizes both efficacy and safety profiles
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 use of these oligonucleotides results in the restoration of at least partial usherin protein activity in photoreceptors, potentially leading to improved vision and delayed progression of retinal degeneration.
Implementation Method 1
an oligonucleotide whose base sequence is complementary to a base sequence in the mutant USH2A target gene transcript
Data Source
AI summary
Among other things, the present disclosure provides USH2A oligonucleotides, and compositions and methods of use thereof, for preventing and/or treating various conditions, disorders or diseases. In some embodiments, provided USH2A oligonucleotides comprise nucleobase modifications, sugar modifications, internucleotidic linkage modifications and/or patterns thereof, and have improved properties, activities and/or selectivities. In some embodiments, the present disclosure provides USH2A oligonucleotides, compositions and methods for preventing and/or treating USH2A-related conditions, disorders or diseases, such as Usher Syndrome (e.g., Usher Syndrome Type 2A), atypical Usher syndrome, or nonsyndromic retinitis pigmentosa.