AAV Anti-VEGF Gene Delivery for Long-Acting Fundus Therapy
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Solution Overview
Problem
Current anti-VEGF therapies for neovascular ophthalmopathy, such as Aflibercept, require frequent injections, leading to side effects, high costs, and poor patient compliance, while long-term treatments risk RPE atrophy and choroidal atrophy.
Innovation Solution
A recombinant AAV vector delivers an Fc-engineered VEGF receptor fusion protein or anti-VEGF antibody for long-term stable expression in the RPE layer, utilizing optimized mutations in the Fc fragment to reduce blood entry and enhance ocular accumulation, allowing one-time administration for lifelong efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-VEGF therapy is administered frequently to maintain efficacy, then treatment effectiveness is improved, but patient compliance deteriorates and side effects increase
Solution Approach 1:
The patent transforms the static protein drug into a dynamic gene therapy system where the therapeutic gene is continuously expressed by RPE cells after single administration, eliminating the need for repeated injections and improving patient compliance while maintaining treatment effectiveness
Solution Approach 2:
The patent delivers the therapeutic gene in advance to RPE cells, which then continuously produce the anti-VEGF protein locally, providing sustained treatment effect without requiring subsequent administrations
2Duration of action of stationary object
If protein drugs are administered repeatedly over long periods, then treatment duration is extended, but RPE atrophy and choroidal atrophy occur
Solution Approach 1:
The patent uses RPE cells as living factories that continuously produce and secrete anti-VEGF protein locally, replacing the need for repeated external protein administrations and thereby avoiding treatment-related atrophy
Solution Approach 2:
The patent enables RPE cells to self-produce the therapeutic protein through delivered genetic instructions, creating a self-sustaining therapeutic system that eliminates the harmful effects of repeated external protein injections
3Duration of action of moving object
If Fc fragment affinity with FcRn is increased to prolong half-life, then drug persistence is improved, but blood entry increases causing systemic safety risks
Solution Approach 1:
The patent modifies the Fc fragment to create differential binding properties: maintains sufficient affinity for FcRn-mediated ocular accumulation and retention while reducing affinity that would promote systemic circulation, achieving localized long-term action without systemic risks
Solution Approach 2:
The patent alters the FcRn binding affinity parameter of the Fc fragment through engineering modifications, optimizing it to achieve the desired balance between ocular persistence and systemic safety
Data Source
AI summary
An rAAV-delivered Fc-engineered VEGF receptor fusion protein or an anti-VEGF antibody is provided and applied to the treatment of angiogenesis-related fundus diseases, such as age-related macular degeneration, wet maculopathy, diabetic retinopathy and other diseases. Based on the aflibercept-expressing gene, the recombinant AAV delivery is used to achieve long-term stable expression of a target gene in the RPE layer by means of genetic modification and vector optimization, thereby delivering an optimized target gene sequence to fundus cells of a patient.