Bispecific Antisense Oligonucleotides for Exon 51 Skipping
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Solution Overview
Problem
Current splice-switching antisense oligonucleotides (AONs) for treating Duchenne Muscular Dystrophy (DMD) have limited therapeutic index and clinical applicability due to factors such as administration route, biostability, biodistribution, and uptake by target cells.
Innovation Solution
A compound comprising two distinct antisense oligonucleotides linked by a linker, specifically targeting sequences within exon 51 of the dystrophin pre-mRNA, to enhance exon 51 skipping efficiency and restore the open reading frame.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If single antisense oligonucleotides are used for exon skipping, then the therapeutic approach is simple and targeted, but the exon skipping efficiency and clinical applicability are limited
Solution Approach 1:
The patent combines two or more antisense oligonucleotides into a single bispecific compound by linking them via a connector group. This merging approach enhances exon skipping efficiency by targeting multiple splice sites simultaneously while maintaining a manageable molecular structure through the use of flexible linkers that allow each oligonucleotide to function independently.
Solution Approach 2:
The invention creates a composite oligonucleotide structure consisting of distinct antisense oligonucleotide segments connected by a chemical linker. This composite design integrates multiple functional elements (different target sequences, chemical modifications) into a single therapeutic molecule that achieves superior exon skipping efficiency compared to individual oligonucleotides.
2Ease of operation
If antisense oligonucleotides are administered systemically, then broad distribution is achieved, but biostability and uptake by target cells remain problematic
Solution Approach 1:
The patent employs chemical modifications of the oligonucleotide sequences, including 2'-O-methyl and phosphorothioate modifications, to enhance biostability and cellular uptake. These parameter changes in the chemical structure protect against nucleases and improve membrane permeability, enabling effective systemic administration while maintaining therapeutic function.
Solution Approach 2:
The connector group serves as an intermediary element that links multiple oligonucleotide sequences while allowing them to maintain their individual binding capabilities. This mediator structure facilitates the coordinated action of multiple antisense sequences against the target pre-mRNA, improving overall therapeutic effectiveness.
3Reliability
If multiple antisense oligonucleotides are used to target different sequences, then exon skipping efficiency improves, but the complexity of the compound increases
Solution Approach 1:
The patent merges multiple antisense oligonucleotides into a single bispecific compound by linking them via a connector group. This merging approach enhances exon skipping efficiency by targeting multiple splice sites simultaneously while maintaining a manageable molecular structure through the use of flexible linkers that allow each oligonucleotide to function independently.
Solution Approach 2:
The connector group design provides a universal platform that can link various combinations of antisense oligonucleotides targeting different sequences. This multi-functional approach allows the same linker architecture to accommodate diverse oligonucleotide pairs, simplifying the overall design while achieving enhanced exon skipping through multiple target sequences.
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 linked antisense oligonucleotide compound demonstrates improved exon 51 skipping efficiencies in muscle cells from DMD patients, potentially leading to increased production of functional dystrophin protein and improved clinical outcomes.
Implementation Method 1
a first antisense oligonucleotide (AON) is complementary to or binds to or targets or hybridizes to or overlaps with at least a part of SEQ ID NO: 3, and wherein said second antisense oligonucleotide (AON) is complementary to or binds to or targets or hybridizes to or overlaps with at least a part of SEQ ID NO: 4
Data Source
AI summary
The current invention provides splice-switching compounds with improved characteristics that enhance clinical applicability preferably for treating, ameliorating, preventing, and/or delaying neuromuscular disorders, more specifically DMD.