AAV2 Capsid Variants for Ocular Transduction Efficiency
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Solution Overview
Problem
Current dependoparvovirus vectors, such as adeno-associated viruses (AAVs), face limitations in ocular transduction efficiency, which hinders their effectiveness in delivering payloads to ocular tissues like the retina and trabecular meshwork.
Innovation Solution
Development of variant dependoparvovirus capsid proteins, specifically AAV2 variants with mutations in the VP1 polypeptide, to enhance ocular transduction efficiency by modifying specific amino acid positions and introducing insertions or substitutions, resulting in improved viral particles for targeted delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type AAV2 capsid proteins are used, then the viral particles can be produced and delivered to cells, but the ocular transduction efficiency is limited and insufficient for effective payload delivery to ocular tissues
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations at defined positions (e.g., K24H, T25M, Y6F, L11F) in the VP1 capsid polypeptide of AAV2. These parameter changes in the capsid protein structure fundamentally alter the viral particle's ability to transduce ocular tissues, transforming it from ineffective (wild-type) to highly effective (variant) for delivering payloads to the retina and trabecular meshwork.
2Adaptability or versatility
If the capsid protein sequence is kept as wild-type AAV2, then the viral structure is stable and producible, but the transduction specificity to ocular tissues like retina and trabecular meshwork is insufficient
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions at specific local positions (e.g., positions 3, 6, 11, 12, 14, 15, 19, 21, 23, 24, 25, 29, 31, 33) within the VP1 capsid polypeptide. Rather than globally modifying the entire capsid structure, these localized changes at specific residues confer enhanced ocular tissue specificity while maintaining overall capsid stability and producibility.
Data Source
AI summary
The disclosure is directed in part to variant capsid polypeptides that can be used to deliver payloads.