Bicistronic AAV Vector for Wet AMD Treatment
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Solution Overview
Problem
Current treatments for wet age-related macular degeneration (AMD) fail to effectively address vascular leakage, fibrosis, and inflammation, leading to persistent vision loss and scarring, with anti-VEGF therapies showing refractoriness and inducing subretinal scars.
Innovation Solution
A genetic construct encoding both an anti-VEGF protein and an anti-fibrotic protein under a single promoter, combined in a recombinant AAV vector, to simultaneously target vascular leakage, fibrosis, and inflammation, allowing for a single administration and long-term therapeutic effect.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If anti-VEGF therapies are used to treat wet AMD, then vascular leakage is reduced, but fibrosis and inflammation persist leading to vision loss and scarring
Solution Approach 1:
The patent combines anti-VEGF protein and anti-fibrotic protein into a single bicistronic genetic construct that is delivered together via recombinant AAV vector. This merging allows simultaneous targeting of both vascular leakage (via anti-VEGF) and fibrosis/inflammation (via anti-fibrotic), resolving the contradiction where anti-VEGF alone reduces leakage but fails to address fibrotic scarring
Solution Approach 2:
The genetic construct serves multiple functions: the anti-VEGF protein component addresses vascular leakage, while the anti-fibrotic protein component addresses fibrosis and inflammation. This multi-functionality in a single construct enables comprehensive treatment of wet AMD pathologies that were previously addressed by separate therapies
2Reliability
If repeated protein injections are administered, then treatment effectiveness is maintained, but treatment burden and cost increase
Solution Approach 1:
The patent replaces repeated mechanical protein injections with a single genetic construct delivery via recombinant AAV vector. The genetic construct expresses therapeutic proteins continuously in the retina, eliminating the need for repeated injections and reducing treatment burden while maintaining effectiveness
Solution Approach 2:
The genetic construct establishes self-sustaining protein expression in the retinal tissue. Once delivered, the construct continuously produces anti-VEGF and anti-fibrotic proteins without requiring external intervention, making the treatment self-service and eliminating repeated administration needs
3Object-affected harmful factors
If single-chain variable fragment antibodies are used, then vascular leakage is targeted, but fibrotic scarring progresses
Solution Approach 1:
The patent merges anti-VEGF single-chain variable fragment antibody with anti-fibrotic protein into a single bicistronic construct. This combination ensures that while vascular leakage is targeted by the anti-VEGF component, the anti-fibrotic component simultaneously prevents and treats fibrotic scarring, resolving the limitation of anti-VEGF alone
Data Source
AI summary
The invention relates to retinal disorders, and to genetic constructs and recombinant vectors comprising such constructs, and their use in gene therapy methods for treating, preventing or ameliorating a wide range of retinal disorders. The constructs and vectors are particularly useful for treating wet age-related macular degeneration (wet-AMD), i.e., neovascular age related macular degeneration. The invention extends to the use of the constructs and vectors for reducing vascular leakage and retinal cell damage. The invention also extends to pharmaceutical compositions per se, and their use in treating, preventing or ameliorating retinal disorders, and for reducing vascular leakage and retinal cell damage.