Oligonucleotide Conjugates for Functional Multi-Exon Skipping
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Solution Overview
Problem
Current methods for treating muscular dystrophies, such as Duchenne muscular dystrophy, face challenges in efficiently skipping multiple exons in the dystrophin pre-mRNA, leading to non-functional or partially functional proteins, and often result in non-productive splicing products.
Innovation Solution
The use of a single oligonucleotide conjugate that stabilizes an exon-containing lariat by hybridizing to specific regions of the pre-mRNA, inducing multi-exon skipping to generate a processed mRNA encoding a truncated and functional protein, thereby improving splicing efficiency and reducing non-productive splicing products.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If current methods are used for treating muscular dystrophies, then treatment can be administered, but splicing efficiency is low and non-productive splicing products are generated
Solution Approach 1:
The invention divides the pre-mRNA target into multiple distinct hybridization regions (first, second, third, and fourth hybridization regions) that bind to specific exons. This segmentation allows selective targeting of individual exons for skipping, improving splicing efficiency by precisely directing the splicing machinery to exclude only the desired exons while preserving the rest of the transcript.
Solution Approach 2:
The oligonucleotide conjugate acts as an intermediary molecule that bridges the splice sites and modulates splicing outcomes. By introducing these exonic hybridization regions as intermediaries, the system redirects the natural splicing process to produce functional truncated proteins instead of non-productive splicing products.
2Adaptability or versatility
If multiple exons are skipped in the dystrophin pre-mRNA, then treatment of muscular dystrophy is achieved, but non-functional or partially functional proteins are produced
Solution Approach 1:
The invention applies local quality by designing hybridization regions with specific binding affinities and locations within exons. Each hybridization region is positioned and configured to target a specific exon or set of exons, allowing precise control over which exons are skipped. This localized targeting ensures that the resulting protein truncation maintains essential functional domains while excluding only the problematic exons.
Solution Approach 2:
The invention utilizes parameter changes by modifying the oligonucleotide conjugate structure, including the sequence, length, and positioning of hybridization regions. By adjusting these parameters, the system can be tuned to achieve specific splicing outcomes that preserve protein functionality while enabling multi-exon skipping for effective muscular dystrophy treatment.
3Productivity
If a single oligonucleotide conjugate is used, then splicing efficiency is improved, but the complexity of designing specific hybridization regions increases
Solution Approach 1:
The invention merges multiple functional elements into a single oligonucleotide conjugate structure. By combining multiple hybridization regions (first, second, third, and fourth regions) into one continuous oligonucleotide molecule, the system achieves coordinated binding to multiple exons simultaneously, thereby improving splicing efficiency while managing design complexity through an integrated rather than fragmented approach.
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 enhances the production of a functional dystrophin protein by effectively skipping multiple exons, offering a more efficient and targeted method for treating muscular dystrophies like Duchenne muscular dystrophy.
Implementation Method 1
a first hybridization region hybridizes to a first target sequence of a pre-mRNA and a second hybridization region hybridizes to a second target sequence of the pre-mRNA
Data Source
AI summary
Disclosed herein are oligonucleotide conjugates and pharmaceutical compositions for inducing multi-exon skipping. In some instances, also disclosed herein are methods of treating a muscular dystrophy, including treating Duchenne muscular dystrophy or Becker muscular dystrophy.