AAV2 Capsid Variants for Retina and Trabecular Meshwork Transduction
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Solution Overview
Problem
Existing adeno-associated dependoparvoviruses (AAVs) face challenges in achieving efficient ocular transduction, particularly in delivering payloads to specific tissues within the eye, such as the retina and trabecular meshwork, with current vectors exhibiting low transduction efficiency.
Innovation Solution
Development of variant capsid polypeptides with specific mutations, such as those corresponding to positions 446-501 in the AAV2 capsid, enhancing ocular transduction by improving the ability of AAVs to target and deliver payloads to ocular tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If wild-type AAV capsid is used, then the virus can infect cells, but the transduction efficiency in ocular tissues is low
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations at positions 446-501 in the AAV2 capsid protein sequence. These mutations alter the physical-chemical properties of the capsid surface, enabling improved binding affinity to ocular tissue receptors while maintaining overall capsid structure and function. The systematic variation of amino acid parameters at key positions resolves the contradiction between general infectivity and ocular-specific transduction efficiency.
Solution Approach 2:
The invention implements local quality by making targeted mutations only in specific regions of the capsid protein (positions 446-501) rather than throughout the entire sequence. This localized modification approach preserves the essential functions of the wild-type capsid while conferring enhanced ocular tropism to the specific region responsible for tissue interaction, thereby maintaining reliability while improving productivity.
2Productivity
If capsid mutations are introduced to improve ocular targeting, then transduction efficiency increases, but the complexity of producing the virus increases
Solution Approach 1:
The patent applies segmentation by dividing the capsid protein into functional regions, with mutations concentrated in the C-terminal domain (positions 446-501) while leaving the N-terminal and central regions unchanged. This segmented approach allows for simplified production strategies where only specific genomic segments need to be modified, reducing the overall complexity of manufacturing compared to comprehensive capsid redesign.
Solution Approach 2:
The invention utilizes copying by creating variant capsids that replicate most of the wild-type sequence unchanged, copying only the essential ocular-targeting motifs from natural variants or through targeted mutagenesis. This approach simplifies manufacturing by allowing production systems to largely replicate proven wild-type production protocols while incorporating only the necessary mutational changes for improved ocular delivery.
Data Source
AI summary
The disclosure is directed in part to variant capsid polypeptides that can be used to deliver payloads.