Antisense Oligonucleotides for DMD Exon Skipping
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Solution Overview
Problem
Current therapies for Duchenne muscular dystrophy (DMD) fail to effectively restore functional dystrophin protein in patients, leading to progressive muscle degeneration and early mortality, as they cannot correct frame-shifting mutations in the DMD gene, which results in the absence of functional dystrophin.
Innovation Solution
The method involves using antisense oligonucleotides (AONs) that bind to continuous stretches of nucleotides within specific exons (43, 46, 50-53) of the DMD pre-mRNA to induce skipping, thereby restoring the open reading frame and promoting the production of functional dystrophin by interfering with splicing signals, allowing for the synthesis of a milder Becker muscular dystrophy (BMD) phenotype.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies are used for DMD, then treatment is provided, but functional dystrophin protein is not restored
Solution Approach 1:
The patent applies parameter changes by modifying the splicing parameters of the DMD pre-mRNA through antisense oligonucleotide treatment. By changing the splicing pattern to skip specific exons (43, 46, 50-53), the therapy transforms the defective transcript into a functional one, restoring the reading frame and enabling dystrophin production.
Solution Approach 2:
The patent uses antisense oligonucleotides as intermediary molecules that bind to specific sequences in the DMD pre-mRNA. These oligonucleotides act as mediators between the defective gene and the desired functional outcome by blocking splice sites and inducing exon skipping, thereby restoring the reading frame without directly modifying the DNA.
2Reliability
If exon skipping is induced in DMD pre-mRNA, then reading frame is restored, but specific splicing signals must be targeted
Solution Approach 1:
The patent applies segmentation by dividing the DMD gene into functional exons and identifying specific splice site sequences within each exon. By targeting individual exons (43, 46, 50-53) with separate antisense oligonucleotides, the therapy segments the complex splicing problem into manageable parts, allowing precise restoration of the reading frame through selective exon skipping.
Solution Approach 2:
The patent applies local quality by designing antisense oligonucleotides with sequences specifically complementary to local splice site regions of exons 43, 46, and 50-53. Each oligonucleotide is tailored to bind to its specific target sequence, creating localized interference that induces skipping of only the intended exon while leaving other splicing events unaffected.
Data Source
AI summary
The invention relates to a method wherein a molecule is used for inducing and/or promoting skipping of at least one of exon 43, exon 46, or exons 50-53 of the DMD pre-mRNA in a patient, the method comprising providing the patient with the molecule. The invention also relates to the molecule as such.