Modified AAV Capsid Muscle Targeting via VP1 Insertion
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Solution Overview
Problem
Current recombinant adeno-associated viral (rAAV) vectors face challenges in achieving optimal biodistribution and expression of genes of interest in muscle tissues, particularly requiring higher doses and lacking specificity for cardiac, skeletal, and smooth muscle targeting.
Innovation Solution
A modified AAV capsid with specific polypeptides inserted between residues 588 and 589 of the wild-type AAV9 VP1 capsid, or corresponding residues in other AAV serotypes, enhances biodistribution and expression of genes of interest in muscle tissues by preferentially targeting cardiac, skeletal, and smooth muscle, while reducing liver expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If wild-type AAV vectors are used for muscle gene delivery, then the vectors can be administered intravenously to reach multiple muscle types, but the biodistribution is not optimal and higher doses are required to achieve sufficient expression
Solution Approach 1:
The patent applies local quality by inserting specific polypeptide sequences (e.g., RGDLGLS, GEARISA, EYRDSSG) at a precise location (residues 588-589 of VP1 capsid) to confer muscle-specific targeting properties to the AAV vector, thereby improving expression efficiency in muscle tissues without affecting other properties of the vector
Solution Approach 2:
The patent changes the biochemical parameters of the AAV capsid by introducing specific amino acid sequences that alter the vector's tissue tropism and binding affinity, enabling preferential uptake by muscle cells and reducing the dose required for therapeutic effect
2Adaptability or versatility
If wild-type AAV vectors are used, then they can deliver genes to multiple muscle types, but they lack specificity for cardiac, skeletal, and smooth muscle targeting
Solution Approach 1:
The patent introduces specific polypeptide sequences at a defined location in the VP1 capsid (residues 588-589) to provide muscle-specific targeting capability, allowing the vector to distinguish and preferentially bind to muscle tissue while maintaining the ability to reach multiple muscle types
Solution Approach 2:
The patent creates a composite capsid structure by combining the wild-type AAV9 VP1 capsid sequence with additional muscle-targeting polypeptide sequences, resulting in a hybrid capsid that exhibits both the systemic distribution capability of AAV9 and enhanced muscle-specific binding affinity
3Reliability
If higher doses of rAAV vectors are administered to achieve sufficient gene expression in muscle, then expression levels improve, but liver expression increases which reduces therapeutic specificity
Solution Approach 1:
The patent applies local quality by inserting specific polypeptide sequences (e.g., RGDLGLS, GEARISA, EYRDSSG) at a precise location (residues 588-589 of VP1 capsid) to confer muscle-specific targeting properties to the AAV vector, thereby improving expression efficiency in muscle tissues without affecting other properties of the vector
Solution Approach 2:
The patent converts the non-specific tropism of wild-type AAV vectors into a benefit by strategically inserting muscle-targeting sequences that redirect the vector's biodistribution preference toward muscle tissues, thereby reducing off-target liver expression while maintaining or enhancing muscle expression at lower doses
Data Source
AI summary
The invention described herein provide a modified VPI capsid enabling preferential targeted expression of gene of interest (GOI) in muscle tissues, as well as recombinant adeno-associated virus (rAAV) with the GOI packaged with the modified VPI capsids, and uses thereof.