AAV2 Capsid VP1 Variants for Retinal RPE Gene Delivery
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Solution Overview
Problem
The development of novel AAV variants with high transduction efficiency into retinal cells is crucial for wider clinical application and is in high demand, as existing AAVs face challenges in effectively delivering therapeutic agents to target sites.
Innovation Solution
A novel AAV variant comprising a capsid variant with specific VP1 amino acid sequences (SEQ ID NOs: 02 to 31) is provided, enhancing delivery efficiency to retinal pigment epithelium (RPE) tissue.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If wild-type AAV is used for gene delivery, then broad tissue tropism is achieved, but transduction efficiency into retinal cells is insufficient
Solution Approach 1:
The patent applies local quality by introducing specific amino acid mutations at particular positions (e.g., positions 533, 554, 561, 588 in VP1; positions 359, 386 in VP3) of the capsid protein sequence. These localized changes modify the surface properties of the capsid to enhance binding affinity to retinal cell receptors, thereby improving transduction efficiency into retinal cells while preserving the overall capsid structure and broad tissue tropism characteristics of wild-type AAV.
2Productivity
If AAV capsid sequence is modified to improve retinal cell targeting, then delivery efficiency to RPE tissue is enhanced, but capsid stability may be compromised
Solution Approach 1:
The patent applies parameter changes by systematically modifying specific amino acid parameters at defined positions in the capsid protein sequence. The mutations (e.g., K533E, Q554K, N561D, Q588K in VP1; Q359E, Q386E in VP3) are designed to optimize electrostatic interactions and hydrophobic bonding with retinal cell surface receptors. These parameter changes are carefully selected to enhance binding affinity while maintaining capsid structural integrity through preservation of the overall protein folding pattern and key structural residues.
Data Source
AI summary
The present disclosure relates to an AAV variant, for example, an AAV2 variant. An AAV variant according to some embodiments of the present disclosure comprises a VP1 variant comprising having any one amino acid sequence selected from SEQ ID NOS: 02 to 31.