AAV Vectors Targeting Corneal Endothelium for Gene Editing
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Solution Overview
Problem
Current methods for delivering gene editing therapeutics to the cornea, particularly for treating corneal dystrophies like Fuchs endothelial corneal dystrophy, are inadequate as they lack specificity and efficiency in targeting the anterior portions of the eye, such as the cornea, leading to potential off-target effects and limited effectiveness.
Innovation Solution
Adeno-associated virus (AAV) vectors are used to deliver CRISPR RNP complexes or gRNA complexes directly to the corneal endothelium, allowing for targeted gene editing by preferentially targeting specific areas of the eye, such as the cornea, using AAV5, AAV6, or AAV8 serotypes that demonstrate tropism to the corneal endothelium, thereby minimizing off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If AAV vectors are used to deliver therapeutics to the eye, then delivery efficiency to the corneal endothelium is improved, but specificity to target only the cornea without affecting other ocular structures is worsened
Solution Approach 1:
The patent applies local quality by engineering AAV vectors with serotype-specific tropism (AAV5, AAV6, or AAV8) that selectively target the corneal endothelium. This allows the therapeutic to be delivered efficiently to the specific tissue (cornea) while minimizing exposure and potential harmful effects to other ocular structures, thus resolving the contradiction between delivery efficiency and specificity.
2Reliability
If gene editing therapeutics are delivered to treat corneal dystrophies, then treatment effectiveness is improved, but off-target effects on other tissues are worsened
Solution Approach 1:
The patent uses serotype-specific AAV vectors (AAV5, AAV6, or AAV8) that exhibit preferential tropism for the corneal endothelium. This localized targeting ensures that gene editing therapeutics are delivered effectively to treat corneal dystrophies while minimizing off-target effects on other tissues, thereby improving treatment reliability without increasing harmful effects.
3Adaptability or versatility
If AAV vectors with broad tropism are used, then delivery to multiple ocular structures is improved, but specificity to the corneal endothelium is worsened
Solution Approach 1:
The patent selects specific AAV serotypes (AAV5, AAV6, or AAV8) that have demonstrated preferential tropism for the corneal endothelium. This approach achieves precise targeting of the corneal endothelium while maintaining the ability to adapt to different therapeutic needs, resolving the contradiction between delivery versatility and targeting precision by using serotype-specific vectors.
Data Source
AI summary
Provided herein are methods for selectively delivering therapeutics to the eye using AAV vectors. For example, the cornea can be specifically targeted using the methods described. Also provided herein are compositions comprising AAV vectors packaged with CRISPR complexes, which can be delivered directly to the eye, for example the cornea, and in particular the cornea endothelium. Diseases and conditions comprising abnormalities or deterioration of tissues in the eye, such as the cornea endothelium (e.g. FECD), can be treated using the methods and compositions described herein.