USH2A Gene Correction via Rare-Cutting Endonuclease Integration
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Solution Overview
Problem
Current gene therapy methods face challenges in delivering and modifying large genes like the USH2A gene, which is involved in Usher syndrome, due to size limitations of delivery vehicles and complex alternative splicing patterns, leading to difficulties in treating monogenic disorders such as retinitis pigmentosa.
Innovation Solution
The development of methods to integrate a transgene into the USH2A gene using rare-cutting endonucleases or transposases, allowing for partial coding sequence substitution and maintenance of isoform production, enabling correction of mutations across the gene while using existing delivery vehicles like adeno-associated viruses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gene replacement therapy is used to treat monogenic disorders, then therapeutic benefits can be provided, but the size of the functional copy of the gene creates delivery challenges
Solution Approach 1:
The patent divides the gene correction approach into segments: instead of delivering the entire large gene, it uses targeted genome editing to correct only the specific mutated regions or critical functional domains within the gene, making the therapeutic payload size-compatible with delivery vehicles while maintaining therapeutic efficacy
2Reliability
If the entire USH2A gene is delivered for gene augmentation, then complete functional replacement is achieved, but current delivery vehicles have size limitations
Solution Approach 1:
The patent extracts only the essential functional elements needed for therapy - either the complete coding sequence (CDS) or critical functional domains - and delivers these extracted sequences using genome editing approaches that integrate them into the patient's genome, bypassing the size limitations of viral delivery vehicles
Solution Approach 2:
The patent transitions from a single-dimension approach (delivering the entire gene as one large unit) to a multi-dimensional strategy by separating the delivery of editing machinery (nucleases, guide RNAs) from the target gene sequence, and by delivering only the minimal necessary corrective sequences rather than the complete gene
3Length of moving object
If methods correct partial regions of a defective gene, then delivery size is reduced, but complex alternative splicing patterns may affect correction effectiveness
Solution Approach 1:
The patent applies local quality by targeting corrections to specific exons or functional domains that are critical for the disease phenotype, rather than attempting to correct the entire gene uniformly, thereby reducing delivery size while maintaining effectiveness despite splicing complexity
Data Source
AI summary
Methods and compositions for modifying the coding sequence of endogenous genes using rare-cutting endonucleases. The methods and compositions described herein can be used to modify the endogenous USH2A gene.