Modified Antisense Oligonucleotides for Dystrophin Exon 53 Skipping
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Solution Overview
Problem
Current antisense oligonucleotides (ASOs) for treating Duchenne muscular dystrophy (DMD) have limited efficacy and are only approved for a small percentage of patients, necessitating the development of more effective exon skipping ASOs.
Innovation Solution
Development of ASOs that are reverse complementary to a portion of exon 53 of human dystrophin pre-mRNA, incorporating modifications such as 2′-O-methoxyethyl (2′-MOE) RNA oligonucleotides with a phosphorothioate backbone, and containing 5-methylcytosine and thymine substitutions, as well as LNA nucleotides, to enhance therapeutic effectiveness.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense oligonucleotides are used for treating DMD, then treatment can be provided to some patients, but efficacy is limited and only a small percentage of patients can be treated
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of oligonucleotides through various substitutions including 2′-O-methyl, 2′-O-methoxyethyl, fluorine, LNA, and PS2 modifications. These chemical parameter changes enhance both the efficacy and stability of the ASOs, enabling them to effectively treat a broader range of DMD patients with different mutation types.
Solution Approach 2:
The patent employs composite materials by combining multiple modified nucleotides within single ASO sequences. The oligonucleotides contain composite structures with 2′-MOE, LNA, fluorinated, and phosphorothioate components working together to achieve enhanced binding affinity, stability, and splice-modulating activity, thereby improving both efficacy and patient coverage.
2Reliability
If ASO sequences are modified to enhance therapeutic effectiveness, then treatment efficacy improves, but molecular complexity increases
Solution Approach 1:
The patent applies local quality by implementing modifications at specific positions within the ASO sequences rather than uniformly throughout. Different nucleotides at different positions receive different modifications (2′-O-methyl, 2′-O-methoxyethyl, fluorine, LNA) based on their functional requirements, optimizing therapeutic effectiveness while managing molecular complexity through targeted rather than comprehensive modification.
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
These modified ASOs demonstrate improved efficacy in delaying the onset and managing symptoms of DMD by specifically targeting and modifying dystrophin pre-mRNA, potentially offering broader treatment applicability than existing ASOs.
Implementation Method 1
ASOs are reverse complementary to a portion of exon 53 of human dystrophin pre-mRNA
Implementation Method 2
Their mechanism of action is aimed at various targets, such as RNaseH-mediated degradation of target RNA in the nucleus or cytoplasm, at splice-modulation (exon inclusion or skipping) in the nucleus
Data Source
AI summary
Provided herein are antisense oligonucleotides (ASOs) that induce skipping of exon 53 of human dystrophin pre-mRNA, and pharmaceutically acceptable derivatives thereof. Also provided are pharmaceutical compositions containing the ASOs and methods of using the ASOs and compositions for treating a subject with Duchenne muscular dystrophy.