Antisense Oligonucleotide Exon Skipping for CEP290 Cryptic Exon
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Solution Overview
Problem
Leber congenital amaurosis, a severe inherited retinal dystrophy causing childhood blindness, is primarily caused by mutations in the CEP290 gene, particularly the c.2991+1655 A>G mutation, which creates a cryptic exon leading to premature stop codon insertion, currently lacking effective therapeutic options.
Innovation Solution
Administration of antisense oligonucleotides complementary to specific nucleic acid sequences to prevent splicing of the cryptic exon in the mutant CEP290 mRNA, employing exon-skipping strategy to restore protein function by blocking splicing reactions and promoting correct mRNA processing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatment methods are used for Leber congenital amaurosis, then the disease progression cannot be halted, but the patients suffer from severe visual deficiency and blindness
Solution Approach 1:
Antisense oligonucleotides are introduced as intermediary molecules that bind to pre-mRNA to modulate splicing. These oligonucleotides act as mediators between the defective gene and the splicing machinery, redirecting splicing to exclude cryptic exons and restore functional protein production, thereby treating the underlying cause rather than just managing symptoms
Solution Approach 2:
The treatment applies preliminary action by intervening at the pre-mRNA splicing stage before the defective protein is produced. By preventing the inclusion of cryptic exons during splicing, the therapy proactively prevents the formation of non-functional or harmful protein variants, addressing the disease mechanism at its earliest molecular stage
2Manufacturing precision
If the cryptic exon is included in the mRNA, then the stop codon is inserted leading to truncated protein, but excluding it requires precise splicing control
Solution Approach 1:
The system employs feedback mechanisms where antisense oligonucleotides are designed to recognize and bind specifically to sequences flanking the cryptic exon. This binding creates a feedback loop that recruits splicing machinery to alternative sites, ensuring accurate exclusion of the cryptic exon while maintaining proper splicing of surrounding exons, thus achieving both precision and functional reliability
Solution Approach 2:
The treatment applies local quality by targeting specific local sequences flanking the cryptic exon with antisense oligonucleotides. Rather than attempting to control entire gene splicing, the therapy focuses locally on the problematic region, modifying splicing decisions only where needed while leaving the rest of the splicing process unchanged, thereby achieving precise control with minimal disruption
3Reliability
If exon skipping strategy is implemented, then CEP290 protein function is restored, but the treatment requires specific oligonucleotide sequences and delivery mechanisms
Solution Approach 1:
The therapy extracts the problematic element by using antisense oligonucleotides to physically block the inclusion of the cryptic exon during splicing. By taking out the defective exon sequence from the mature mRNA through selective exclusion, the treatment restores protein function by ensuring only the correct coding sequences are translated, while the complex delivery mechanisms are merely vehicles to deliver this extraction mechanism
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 oligonucleotide-mediated exon skipping strategy effectively ameliorates Leber congenital amaurosis symptoms by restoring CEP290 protein function and stability, improving visual acuity and cilia assembly, with potential benefits ranging from 10% to 100% compared to non-treated patients.
Implementation Method 1
administering to said patient at least one antisense oligonucleotide complementary to nucleic acid sequence that is necessary for preventing splicing of the cryptic exon
Data Source
AI summary
The present invention relates to a method for treating a Leber congenital amaurosis in a patient harbouring the mutation c.2991+1655 A>G in the CEP290 gene, comprising the step of administering to said patient at least one antisense oligonucleotide complementary to nucleic acid sequence that is necessary for preventing splicing of the cryptic exon inserted into the mutant c. 2991+1655 A>G CEP290 mRNA.