AAV Anti-VEGF Constructs for Local Vestibular Schwannoma Therapy
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Solution Overview
Problem
Existing treatments for conditions associated with neovascularization, such as vestibular schwannoma, face challenges in achieving proper local delivery of anti-VEGF proteins like ranibizumab, bevacizumab, and aflibercept, as systemic administration may not ensure adequate levels at the target sites.
Innovation Solution
The use of recombinant AAV constructs encoding anti-VEGF proteins, particularly with an rAAV Anc80 capsid, to deliver these proteins locally to the ears and eyes, utilizing inducible, constitutive, or tissue-specific promoters to ensure targeted expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If systemic administration of anti-VEGF proteins is used, then broad coverage is achieved, but adequate local levels at target sites cannot be ensured
Solution Approach 1:
The patent uses recombinant AAV vectors as intermediary carriers to deliver anti-VEGF protein coding sequences to target cells. The AAV vector acts as a mediator that transports the therapeutic gene to the specific tissue (cochlea), enabling local production of the anti-VEGF protein without requiring direct systemic administration, thus achieving high local concentrations while simplifying the delivery process.
Solution Approach 2:
The invention enables the target tissue to produce the anti-VEGF protein itself through genetic modification. By introducing the coding sequence into cochlear cells via AAV, the cells become self-sufficient producers of the therapeutic protein, continuously generating it locally without requiring repeated external administrations. This resolves the contradiction by achieving sustained local high concentrations through the tissue's own production capability.
2Quantity of substance
If recombinant AAV constructs are used for local delivery, then adequate local levels are achieved, but device complexity increases
Solution Approach 1:
The recombinant AAV construct is designed with multiple functional elements integrated into a single vector system: the capsid provides targeted cell entry, the promoter enables tissue-specific or inducible expression, and the coding sequence delivers the therapeutic payload. This multi-functional design achieves adequate local protein levels while consolidating complexity into a standardized, well-characterized vector platform that can be produced and administered using established protocols.
3Quantity of substance
If local delivery is implemented, then proper levels at target sites are achieved, but treatment applicability to various conditions is limited
Solution Approach 1:
The patent incorporates inducible promoters (such as tetracycline-responsive or heat-shock promoters) that allow dynamic control of anti-VEGF protein expression. The expression level can be adjusted on-demand by applying the appropriate inducer, enabling the same local delivery construct to adapt to different treatment requirements, disease stages, or patient responses. This dynamic control enhances treatment versatility while maintaining high local concentrations when needed.
Data Source
AI summary
The present disclosure provides a construct comprising a coding sequence operably linked to a promoter, wherein the coding sequence encodes a vascular endothelial growth factor (VEGF) binding agent or a portion thereof. In some embodiments, a construct is an AAV construct. In some embodiments, an AAV construct is a part of an AAV particle. Compositions comprising constructs and AAV particles described herein can be useful in treating hearing loss, for example, hearing loss associated with vestibular schwannoma.