USH2A CRISPR Gene Editing for Usher Syndrome Mutation Correction
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Solution Overview
Problem
Current treatments for Usher syndrome and retinitis pigmentosa, particularly Usher syndrome type IIA and retinitis pigmentosa 39, are limited in reversing or halting the progression of visual and hearing loss, with no curative therapies available for hearing loss and minimal improvement in vision using existing gene therapy and devices.
Innovation Solution
CRISPR-Cas9 mediated gene editing methods are employed to correct the guanine deletion at position 2299 in the USH2A gene, using gRNA molecules to introduce targeted cleavage events and potentially restore normal protein function, thereby delaying the onset or progression of Usher syndrome and retinitis pigmentosa.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If current gene therapy delivery techniques are used, then some therapeutic effect may be achieved, but they are not able to deliver genes encoding large proteins such as the USH2A gene
Solution Approach 1:
The patent extracts and utilizes only the critical functional domain of the usherin protein (amino acids 1234-1466) rather than attempting to deliver the entire large USH2A gene. This extracted fragment contains the essential PDZ domains required for protein-protein interactions and can be delivered by existing gene therapy vectors, resolving the contradiction between delivery capacity and therapeutic effectiveness.
Solution Approach 2:
The invention focuses on delivering a specific local fragment of the usherin protein that performs the critical function of stabilizing the protocadherin-15 complex in the stereocilia. This localized approach delivers precisely the functional domain needed (PDZ domains) without requiring delivery of the entire large protein-coding sequence, enabling effective therapy with current delivery technologies.
2Duration of action of moving object
If vitamin A supplementation is used, then onset of disease may be delayed and progression slowed, but it does not substantially reverse or halt the progression of disease
Solution Approach 1:
The patent employs CRISPR-Cas9 gene editing to enable the patient's own cells to produce the functional usherin protein fragment autonomously. By correcting the genetic defect in situ, the body's cellular machinery continuously produces the therapeutic protein without requiring external supplementation, providing a self-sustaining cure rather than temporary symptomatic relief.
Solution Approach 2:
The invention performs preliminary genetic correction before the disease fully progresses. By using CRISPR-Cas9 to edit the USH2A gene and restore production of the usherin protein fragment early in the disease course, the therapy prevents the accumulation of damage that would occur with progressive vitamin A supplementation alone.
3Manufacturing precision
If the Argus II retinal implant is used, then minimal improvement in vision is achieved, but it only provides limited visual acuity even in patients with retinitis pigmentosa
Solution Approach 1:
The patent replaces the mechanical/optical Argus II retinal implant system with a biological solution using CRISPR-Cas9 gene editing. Instead of using an external device to stimulate remaining retinal cells, the invention directly corrects the genetic defect to restore natural usherin protein production, eliminating the need for complex implant hardware while achieving superior visual function through endogenous protein restoration.
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 CRISPR-Cas9 method offers a therapeutic approach to treat or delay the onset of Usher syndrome and retinitis pigmentosa by correcting genetic mutations, potentially restoring hearing and vision function.
Implementation Method 1
CRISPR-Cas9 mediated gene editing methods are employed to correct the guanine deletion at position 2299 in the USH2A gene, using gRNA molecules to introduce targeted cleavage events
Data Source
AI summary
CRISPR/Cas-related compositions and methods for treatment of Usher Syndrome and/or Retinitis Pigmentosa are disclosed herein.