Modified AAV2 Capsids for Targeted Retinal Cell Delivery
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Solution Overview
Problem
Existing AAV vectors face limitations in efficiently delivering nucleic acid to specific retinal cell types and regions, leading to suboptimal expression levels, particularly in foveal cones and other retinal cells.
Innovation Solution
Development of AAV2 vectors with modified capsid polypeptides, as described in Table 1 or Formula A, that enhance the ability to infect and express exogenous nucleic acid in retinal cells, including foveal cones, retinal ganglion cells, photoreceptor cells, and bipolar cells, achieving higher expression levels compared to wild-type AAV2 vectors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type AAV2 vectors are used for nucleic acid delivery to retinal cells, then the vectors can infect retinal cells and deliver nucleic acid, but the expression levels in specific cell types (particularly foveal cones) are suboptimal
Solution Approach 1:
The patent applies parameter changes by modifying the capsid polypeptide amino acid sequence of AAV2 vectors. Specific mutations in the capsid protein (such as at positions 587-588 or other residues) alter the vector's properties to enhance its ability to infect specific retinal cell types and increase nucleic acid expression levels, directly resolving the contradiction between delivery efficiency and expression productivity
Solution Approach 2:
The invention applies local quality by creating capsid variants with specific localized amino acid modifications that target particular retinal cell types (e.g., foveal cones, photoreceptors, bipolar cells). These localized changes in capsid structure enable selective enhancement of infectivity and expression in specific cellular compartments while maintaining overall vector functionality
2Reliability
If existing AAV vectors are used, then they can deliver nucleic acid to retinal cells, but the delivery efficiency to specific retinal regions and cell types is insufficient
Solution Approach 1:
The patent creates AAV capsid variants with specific amino acid modifications that confer localized targeting capabilities to different retinal cell types and regions. By introducing specific mutations in the capsid protein sequence, the vectors gain enhanced adaptability to target foveal cones, photoreceptors, bipolar cells, and other specific retinal compartments while maintaining reliable nucleic acid delivery
Solution Approach 2:
The invention modifies capsid polypeptide parameters (amino acid sequence, charge distribution, hydrophobicity) to enhance the vector's adaptability to specific retinal tissues. These parameter changes enable the vectors to overcome the limitations of wild-type AAV2 and achieve broader and more specific tropism across different retinal cell types
Data Source
AI summary
This document relates to AAV vectors (e.g., AAV2 vectors). For example, AAV vectors (e.g., AAV2 vectors) containing an AAV capsid polypeptide that includes an amino acid sequence set forth in Table 1 (or a variant thereof) or Formula A, such AAV capsid polypeptides, nucleic acid molecules encoding such vectors, nucleic acid molecules encoding such AAV capsid polypeptides, host cells containing and/or expressing such nucleic acid molecules, and methods and materials for making or using such vectors and/or AAV capsid polypeptides are provided.