AAV Capsid Peptide Insertion for Retargeting
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Solution Overview
Problem
Current strategies for developing effective vaccines against infectious diseases like COVID-19 and cancer face challenges in achieving long-term immunity and specificity, particularly in redirecting adeno-associated virus (AAV) tropism to target cell types effectively, especially with larger peptide insertions which can compromise structural integrity and infectivity.
Innovation Solution
The insertion of immunogenic proteins or protein portions of varying lengths, up to 400 amino acids, into surface-exposed positions of AAV capsids at variable regions VIII and IV, allowing for high-density display and potential retargeting by incorporating linker sequences, enabling the AAV vector to serve as a subunit vaccine or gene therapy vehicle.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If larger peptide insertions are introduced into AAV capsids to enhance immune response, then immunogenicity is improved, but structural integrity and infectivity are compromised
Solution Approach 1:
The patent applies local quality by selecting specific surface-exposed positions (variable regions IV and VIII) on the AAV capsid for peptide insertion. These locations were chosen because they are naturally variable and surface-accessible, allowing immunogenic peptides to be displayed without disrupting the core structural integrity of the capsid. This localized modification approach enables high-density peptide display while preserving overall capsid stability and infectivity.
2Adaptability or versatility
If peptide insertions are made at surface-exposed positions to redirect AAV tropism, then cell targeting specificity is improved, but capsid stability deteriorates
Solution Approach 1:
The patent targets specific surface-exposed variable regions (IV and VIII) of the AAV capsid for peptide insertion to redirect tropism. These locations are naturally variable and accessible, allowing cell-type-specific peptides to be displayed without compromising capsid stability. The variable regions serve as ideal local sites for functional modification while preserving overall structural integrity.
Solution Approach 2:
The patent employs parameter changes by modifying the amino acid sequence at specific capsid positions through peptide insertion. This changes the surface properties and binding characteristics of the capsid, enabling retargeting to different cell types. The modifications are limited to specific variable regions, maintaining the physical-chemical parameters of the overall capsid structure within stable ranges.
3Reliability
If multiple immunogenic peptides are displayed at high density on AAV surface, then vaccine efficacy is improved, but manufacturing complexity increases
Solution Approach 1:
The patent achieves high-density display of multiple immunogenic peptides by utilizing the 60-copy icosahedral symmetry of the AAV capsid. Each of the 60 capsid proteins can potentially carry peptide inserts at variable regions IV and VIII, enabling simultaneous display of multiple immunogenic targets. This multi-functional display approach enhances vaccine efficacy while relying on the self-assembly properties of the capsid to simplify manufacturing.
Solution Approach 2:
The patent segments the immunogenic content by dividing it into multiple discrete peptide inserts that can be independently designed and inserted at different variable regions. This segmentation allows for modular construction of multi-valent vaccines, where each peptide can be optimized separately and then assembled into the complete capsid structure through standardized manufacturing protocols.
Data Source
AI summary
The present invention relates to an adeno-associated vims (AAV) or an adeno-associated virus-like particle (AAVLP), comprising an insert of about 75-400 amino acids in the viral proteins (VPs) VP1, VP2 and/or VP3 at an insertion site (I) at the top of variable region VIII and/or variable region IV (VR-VIII and/or VR-IV) of the VP, wherein the insert is an immunogenic protein or a portion thereof and/or wherein the insert is a protein comprising a binding domain, such as an antigen-binding domain specific for a target antigen. The present invention also relates to pharmaceutical compositions comprising said AAV or AAVLP and to the pharmaceutical composition or the AAV or AAVLP for use in therapy, particularly for use as a vaccine, for use in the treatment or the prevention of a diseases and/or for use in gene therapy. Also concerned is a method for producing the AAV of AAVLP of the present invention.