Antisense Oligomer Modulates OPA1 Splicing to Restore Protein Levels
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for autosomal dominant optic atrophy (ADOA) are lacking, as there is no approved disease-modifying therapy, and existing therapies do not effectively address the mitochondrial deficits leading to progressive vision loss.
Innovation Solution
A method is described to modulate the expression of the OPA1 protein in cells by using an agent, such as an antisense oligomer, that targets and modifies the splicing of a non-sense mediated RNA decay-inducing exon (NMD exon) from the pre-mRNA, thereby increasing the level of processed mRNA and OPA1 protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If alternative splicing events occur in the OPA1 gene, then non-productive mRNA transcripts are generated, but functional protein expression is reduced or abolished
Solution Approach 1:
The patent converts the harmful alternative splicing event that produces non-productive mRNA into a beneficial outcome by using antisense oligomers to block the aberrant splicing. The ASOs specifically target the alternative splice sites, preventing the formation of non-productive transcripts and thereby converting the pathological splicing mechanism into a therapeutic opportunity to restore functional OPA1 protein expression
Solution Approach 2:
The antisense oligomer serves as an intermediary molecule that mediates between the aberrant pre-mRNA and the splicing machinery. The ASO binds to specific sequences in the pre-mRNA, acting as a molecular mediator that redirects the splicing process to produce productive mRNA transcripts instead of non-productive ones, thereby restoring functional protein expression
2Reliability
If a non-sense mediated RNA decay-inducing exon is included in pre-mRNA, then aberrant protein expression occurs, but functional protein levels are reduced
Solution Approach 1:
The patent extracts or removes the harmful NMD-inducing exon from the pre-mRNA transcript through targeted splicing modulation. The antisense oligomer directs the splicing machinery to exclude this specific exon that contains the premature stop codon, thereby extracting the source of non-sense mediated decay and restoring production of full-length functional OPA1 protein
Solution Approach 2:
The patent converts the harmful presence of the NMD-inducing exon into a beneficial therapeutic effect by using the antisense oligomer to specifically target and exclude this exon. The ASO transforms the pathological splicing event into a controlled process that eliminates the harmful exon while preserving the coding sequence, thereby converting a disease mechanism into a therapeutic strategy
3Reliability
If no disease-modifying treatment is available for ADOA, then patient outcomes remain unchanged, but mitochondrial deficits progress
Solution Approach 1:
The patent applies preliminary action by targeting the splicing process at the pre-mRNA level, before translation and protein function are affected. By correcting the splicing defect early in the gene expression pathway, the treatment prevents the formation of non-functional proteins and restores mitochondrial function before irreversible damage occurs, addressing the disease progression proactively rather than reactively
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 method achieves a significant increase in the level of processed mRNA and OPA1 protein expression, potentially alleviating the symptoms of ADOA by enhancing mitochondrial function and reducing aberrant protein expression.
Implementation Method 1
the agent comprises an antisense oligomer with at least 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 6-275 and 280-299
Implementation Method 2
the agent modulates splicing of the NMD exon from the pre-mRNA, thereby modulating a level of processed mRNA that is processed from the pre-mRNA
Data Source
AI summary
Alternative splicing events in genes can lead to non-productive mRNA transcripts which in turn can lead to aberrant protein expression, and therapeutic agents which can target the alternative splicing events in genes can modulate the expression level of functional proteins in patients and/or inhibit aberrant protein expression. Such therapeutic agents can be used to treat a condition or disease caused by protein deficiency and/or mitochondrial function deficit.