OPA1 Pre-mRNA Trans-Splicing for Endogenous Isoform Correction
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Solution Overview
Problem
Current treatments for hereditary optic neuropathies associated with OPA1 gene mutations, such as Autosomal Dominant Optic Atrophy (ADOA), Autosomal Dominant Optic Atrophy Plus (ADOA+), and Behr's Syndrome, lack effective disease-modifying therapies that can fine-tune the expression of OPA1 protein isoforms to address visual loss and associated symptoms.
Innovation Solution
A gene therapy approach using Spliceosome-Mediated RNA Trans-splicing (SMART) to target specific intronic and exonic sequences in mutated OPA1 pre-messenger RNA (pre-mRNA) with therapeutic molecules that trans-splice the RNA to correct mutations, maintaining endogenous regulation of OPA1 isoforms and correcting nearly 90% of known pathogenic mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AAV-delivered OPA1 isoform 1 is used for gene therapy, then OPA1 expression is restored, but visual acuity does not significantly improve and mitochondrial dysfunction occurs
Solution Approach 1:
The patent segments the OPA1 gene therapy approach by using trans-splicing molecules that target specific mutated exons rather than delivering the entire OPA1 isoform 1 gene. This allows selective correction of pathogenic mutations while preserving the natural regulation and splicing of the endogenous OPA1 gene, thereby restoring functional OPA1 expression without the adverse effects of overexpressing a single isoform.
Solution Approach 2:
The patent introduces pre-mRNA trans-splicing molecules as intermediaries that bind to mutated OPA1 pre-mRNA and facilitate exon replacement. These trans-splicing molecules act as mediators between the defective endogenous gene and the desired functional outcome, enabling precise correction of mutations without directly delivering foreign gene sequences that could cause mitochondrial dysfunction.
2Reliability
If pre-mRNA trans-splicing molecules are used to correct OPA1 mutations, then nearly 90% of pathogenic mutations are corrected, but the complexity of the therapy increases
Solution Approach 1:
The patent designs pre-mRNA trans-splicing molecules with universal applicability to correct nearly 90% of different OPA1 pathogenic mutations through a single therapeutic mechanism. The trans-splicing molecules can target multiple mutation types (nonsense, missense, frameshift) across different exons, providing a multi-functional solution that reduces the need for multiple specialized therapies.
3Reliability
If OPA1 isoform 1 is overexpressed to compensate for mutations, then some mitochondrial dysfunction is corrected, but the mitochondrial network becomes altered and more deleterious
Solution Approach 1:
The patent enables the endogenous OPA1 gene to serve itself by utilizing the cell's own splicing machinery to process and correct the mutated pre-mRNA. The trans-splicing molecules facilitate this self-correction process, allowing the cell to produce functional OPA1 proteins through its natural regulatory pathways, thereby avoiding the harmful effects of external overexpression on mitochondrial network organization.
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 approach effectively corrects OPA1 transcripts and protein isoforms, potentially restoring visual function and addressing associated symptoms like sensorineural deafness and polyneuropathy, with minimal impact on mitochondrial networks.
Implementation Method 1
employing pre-mRNA trans-splicing molecules to correct OPA1 transcripts by replacing defective exons with functional ones
Data Source
AI summary
The present invention provides pre-mRNA trans-splicing molecules (RTMs) that are useful for correcting mutations in the OPA1 gene. Also provided are methods of using the RTMs as gene therapy (e.g., ex vivo and in vivo gene therapy) for the treatment or prevention of diseases or disorders associated with OPA1 mutations.