rAAV Anti-VEGF Constructs for Vestibular Schwannoma Treatment
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Solution Overview
Problem
Current methods for administering anti-VEGF proteins to treat conditions associated with neovascularization are not effective in providing sufficient local concentrations of these proteins at the affected cells and tissues.
Innovation Solution
The use of recombinant AAV (rAAV) constructs encoding anti-VEGF proteins, specifically with a rAAVAnc80 capsid, to form rAAVAnc80-antiVEGF particles, which can be administered to provide localized expression of anti-VEGF proteins in the ears and eyes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If anti-VEGF proteins are administered systemically, then they can reach affected tissues, but insufficient local concentrations are achieved at the target cells and tissues
Solution Approach 1:
The patent employs rAAV vectors with tissue-specific promoters (e.g., AFO1, RCAN1) to drive localized expression of anti-VEGF proteins specifically in the inner ear and affected tissues. This ensures high local concentrations of the therapeutic protein at the target site while minimizing systemic distribution, thereby resolving the contradiction between achieving sufficient local concentration and treatment effectiveness.
Solution Approach 2:
The rAAV vector serves as an intermediary delivery system that carries the anti-VEGF protein coding sequence to target cells. The vector mediates localized gene expression, enabling sustained production of anti-VEGF protein directly at the site of neovascularization, thus achieving both high local concentration and reliable therapeutic effect.
2Quantity of substance
If high doses of anti-VEGF proteins are administered, then sufficient local concentrations can be achieved, but systemic side effects increase
Solution Approach 1:
By using tissue-specific promoters (AFO1 for inner ear, RCAN1 for retina) within the rAAV vector, the patent achieves localized expression of anti-VEGF protein only in the affected tissues. This eliminates the need for high systemic doses, thereby preventing systemic side effects while maintaining sufficient local concentrations for effective treatment.
Solution Approach 2:
The rAAV vector enables the target tissues to produce their own anti-VEGF protein through localized gene expression. This self-service mechanism ensures continuous local production of the therapeutic protein without requiring repeated systemic administrations, thus avoiding cumulative systemic side effects.
3Productivity
If short-acting anti-VEGF protein administration is used, then treatment can be initiated quickly, but sustained local concentrations cannot be maintained
Solution Approach 1:
The rAAV vector is pre-engineered with the anti-VEGF protein coding sequence and tissue-specific promoter before administration. Once delivered to target cells, it immediately begins transcribing and translating the therapeutic protein, providing both rapid initiation and sustained local concentrations without requiring repeated injections.
Solution Approach 2:
The rAAV-mediated gene expression establishes continuous local production of anti-VEGF protein in the target tissues. This continuous action maintains sustained therapeutic concentrations over time, eliminating the intermittent gaps associated with repeated systemic administrations while keeping treatment initiation simple and rapid.
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.