Antisense Oligonucleotides Modulate ATP7B Splicing for Wilson Disease
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Solution Overview
Problem
Current treatments for Wilson disease, such as chelation therapy, are associated with adverse effects and discontinuation due to gastrointestinal side effects and immune reactions, and previous analyses of the M645R mutation in the ATP7B gene have not considered the impact of aberrant splicing on copper homeostasis.
Innovation Solution
Development of antisense oligonucleotides that are at least 70% complementary to ATP7B exon 6 or its flanking introns to modulate splicing, specifically targeting splicing regulatory elements to increase exon 6 inclusion in ATP7B mRNA, thereby improving copper handling and reducing urinary copper levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chelation therapy is used to treat Wilson disease, then copper excretion is improved, but adverse effects and discontinuation rates increase
Solution Approach 1:
The patent uses antisense oligonucleotides as intermediaries to modulate splicing of ATP7B pre-mRNA, thereby indirectly affecting copper handling. Instead of directly chelating copper (which causes adverse effects), the oligonucleotides act as mediators that restore proper splicing of the ATP7B gene, leading to improved copper excretion through the naturally functioning transporter protein.
2Reliability
If zinc salts are used for maintenance treatment, then copper absorption is blocked, but adherence difficulties and gastrointestinal side effects occur
Solution Approach 1:
The antisense oligonucleotides enable the body's own cellular machinery to correct the splicing defect. By targeting the molecular defect directly, the treatment leverages the cell's inherent splicing mechanisms to produce functional ATP7B protein, potentially reducing the need for long-term adherence to complex maintenance regimens.
3Reliability
If splicing modulation is targeted to increase exon 6 inclusion, then copper handling is improved, but treatment complexity increases
Solution Approach 1:
The antisense oligonucleotides are designed to target specific local regions (splicing regulatory elements) within the ATP7B pre-mRNA molecule. By focusing the therapeutic action on precise local sequences that control exon 6 inclusion, the treatment achieves specific modulation of splicing without requiring complex systemic interventions.
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 antisense oligonucleotides effectively increase exon 6 inclusion in ATP7B mRNA, potentially reducing adverse effects of Wilson disease by enhancing copper excretion and improving copper tolerance, offering a more stable treatment option compared to traditional chelation therapies.
Implementation Method 1
an oligonucleotide including a nucleobase sequence complementary to a sequence within ATP7B exon6, a flanking intron, or a combination thereof
Data Source
AI summary
The present disclosure provides antisense oligonucleotides, compositions, and methods that target ATP7B exon 6 or a flanking intron, thereby modulating splicing of ATP7B pre-mRNA to increase the level of ATP7B mRNA molecules having exon 6, e.g., to provide a therapy for Wilson disease. The present disclosure provides an antisense oligonucleotide including a nucleobase sequence at least 70% complementary to an ATP7B target sequence in exon 6, a 5′-flanking intron, a 3′-flanking intron, or a combination of exon 6 and the 5′-flanking or 3′-flanking intron.