AAV2 Capsid Variants for Efficient Ocular Cell Transduction
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Solution Overview
Problem
Current recombinant AAV vectors face challenges with low transduction efficiency and restricted tissue tropisms, limiting their application as feasible and efficacious therapies, and there is a concern about faithful clinical translation of non-human AAV serotypes.
Innovation Solution
Development of recombinant AAVs with capsid protein variants, such as AAV v149, AAV v152, AAV v175, and AAV v182, featuring specific amino acid substitutions at positions E36, D80, V125, D213, and M604, which enhance packaging efficiency and tropism for ocular cells, allowing for efficient delivery of transgenes to cells like amacrine, bipolar, and retinal cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If wild-type AAV2 capsid protein is used, then the vector can be produced, but transduction efficiency is low and tissue tropism is restricted
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid positions (E36, D80, V125, D213, M604) in the AAV2 capsid protein sequence. These parameter changes at the molecular level result in altered tissue tropism and enhanced transduction efficiency, transforming the vector's ability to target ocular cells while maintaining producibility
Solution Approach 2:
The invention applies local quality by introducing site-specific amino acid substitutions at defined positions within the capsid protein. Rather than globally altering the entire capsid structure, localized changes at specific residues (E36G, D80N, V125A, D213G, M604T) confer enhanced ocular cell targeting capability while preserving overall capsid function and assembly
2Productivity
If non-human AAV serotypes are used to improve transduction efficiency, then gene delivery is enhanced, but clinical translation is compromised due to immunogenicity concerns
Solution Approach 1:
The patent modifies the AAV2 capsid protein through targeted amino acid substitutions to achieve enhanced ocular cell transduction. By making parameter changes within the human AAV2 sequence rather than using non-human serotypes, the invention maintains clinical translation fidelity while improving gene delivery efficiency to ocular tissues
Solution Approach 2:
The invention creates a modified version of the human AAV2 capsid protein by copying the wild-type sequence and introducing specific amino acid substitutions. This approach produces a human-compatible vector with enhanced functionality, avoiding the immunogenicity issues associated with non-human AAV serotypes while retaining improved transduction capabilities
3Productivity
If capsid protein variants with multiple amino acid substitutions are created, then packaging efficiency and transduction are improved, but vector complexity increases
Solution Approach 1:
The patent applies local quality by introducing site-specific amino acid substitutions at defined positions within the capsid protein. Rather than globally altering the entire capsid structure, localized changes at specific residues (E36G, D80N, V125A, D213G, M604T) confer enhanced ocular cell targeting capability while preserving overall capsid function and assembly
Solution Approach 2:
The patent applies parameter changes by modifying specific amino acid positions (E36, D80, V125, D213, M604) in the AAV2 capsid protein sequence. These parameter changes at the molecular level result in altered tissue tropism and enhanced transduction efficiency, transforming the vector's ability to target ocular cells while maintaining producibility
Data Source
AI summary
Aspects of the disclosure relate to compositions and methods for delivering a transgene (e.g., a transgene encoding one or more gene products) to a target cell (e.g., an ocular cell). The disclosure is based, in part, on adeno-associated virus (AAV) capsid protein variants and methods of using same for delivery of a transgene.