CRISPR-Cas9 MYOC Knockout for Glaucoma Treatment
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Solution Overview
Problem
Current glaucoma therapies focus on lowering intraocular pressure (IOP) but do not directly address the underlying pathogenesis of the disease and often require poor patient compliance due to the need for frequent eye drop administration, which complicates long-term care.
Innovation Solution
The use of the CRISPR-Cas9 system with guide-RNAs specific for the myocilin gene to inactivate the myocilin gene in the trabecular meshwork, employing an adeno-associated virus (AAV) vector to knock out mutant MYOC expression, thereby reducing IOP and reversing ocular hypertension.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stress or pressure
If current glaucoma therapies (pharmacological and surgical) are used to lower IOP, then IOP reduction is achieved, but the underlying TM pathogenesis is not addressed and efficacy is lost over time
Solution Approach 1:
The patent extracts and eliminates the root cause of the disease by using CRISPR-Cas9 genome editing to knock out the MYOC gene in trabecular meshwork cells, removing the pathogenic mechanism rather than merely suppressing its effects. This genetic modification permanently eliminates the defective protein production that causes TM damage and IOP elevation.
Solution Approach 2:
The patent performs preliminary genetic editing of the MYOC gene before the disease progresses to irreversible damage. By introducing CRISPR-Cas9 vectors early in the disease course, the therapy prevents pathogenic protein accumulation and TM fibrosis from developing in the first place, rather than treating advanced disease stages.
2Stress or pressure
If topical ocular pharmaceutical therapies are administered one to multiple times per day, then IOP control is maintained, but patient compliance deteriorates and long term care is complicated
Solution Approach 1:
The patent enables the trabecular meshwork to correct its own pathology through autonomous gene expression modification. The CRISPR-Cas9 system, once delivered via AAV vector, allows the TM cells to self-edit their own MYOC gene, eliminating the need for external pharmaceutical intervention and establishing long-term self-regulation of IOP.
Solution Approach 2:
The patent performs the therapeutic action once during an initial procedure, establishing permanent genetic correction that eliminates the need for daily eye drop administration. This single preliminary intervention prevents the recurring need for patient compliance with multiple daily dosings.
3Reliability
If CRISPR-Cas9 genome editing is used to knock out MYOC, then a one-time cure is achieved, but the complexity of gene delivery vectors must be managed
Solution Approach 1:
The patent uses an adeno-associated virus (AAV) vector as an intermediary carrier to deliver the CRISPR-Cas9 editing components into trabecular meshwork cells. The AAV vector serves as a biocompatible mediator that facilitates genetic modification without integrating into the host genome, thereby enabling safe and effective gene editing with controlled delivery.
Solution Approach 2:
The patent optimizes various parameters of the AAV vector system, including serotype selection (AAV2, AAV5, AAV8), dosage, and timing of administration, to achieve efficient delivery and expression of CRISPR-Cas9 components in the trabecular meshwork while minimizing off-target effects and ensuring long-term therapeutic stability.
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
This approach provides a one-time cure by normalizing the trabecular meshwork and IOP, improving outflow facility and retinal ganglion cell function, and eliminating the need for ongoing medication adherence.
Implementation Method 1
The disclosure provides composition and methods for genome editing, e.g., using the CRISPR-Cas9 system and guide-RNA (gRNA) specific for the myocilin gene, to, in one example, inactivate the myocilin gene
Implementation Method 2
transduction of the TM with a vector encoding CRISPR-Cas9 and gRNA knocks out expression of MYOC in the TM
Data Source
AI summary
A vector and methods of using the vector for, for example, to prevent, inhibit or treat glaucoma, decrease intraocular pressure or to reduce MYOC expression in a mammal, are provided.