Engineered AAV9 Capsid for Cardiac Tropism and Lower Liver Uptake
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Solution Overview
Problem
Existing adeno-associated virus (AAV) vectors, particularly AAV9, face challenges in achieving efficient and selective transduction of cardiac tissues while minimizing liver transduction, often requiring high doses that can lead to systemic inflammation and toxicity.
Innovation Solution
Development of recombinant AAV capsid proteins with engineered variant polypeptide sequences at specific sites, such as VR-IV, VR-V, VR-VII, and VR-VIII, to enhance cardiac tropism and selectivity, using methods like directed evolution and chimeric capsid design.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AAV9 vector is used for cardiac transduction, then moderate cardiac transduction is achieved, but majority of vector trafficks to the liver and high systemic doses are required
Solution Approach 1:
The patent applies local quality by modifying specific regions of the capsid protein (variable regions VR-IV, VR-V, VR-VII, VR-VIII) to create localized changes in binding affinity. These targeted mutations enable the capsid to preferentially bind to cardiac tissue receptors while reducing affinity for liver receptors, achieving tissue-specific transduction without requiring high systemic doses
Solution Approach 2:
The patent changes the biochemical parameters of the capsid protein by introducing variant polypeptide sequences at specific positions. These parameter changes alter the capsid's interaction with cellular receptors, transforming the vector's tropism from liver-preferring to cardiac-preferring, thereby reducing off-target effects and systemic toxicity
2Reliability
If high systemic doses of AAV9 are administered to achieve therapeutic cardiac transduction, then cardiac transduction levels are improved, but systemic inflammation and toxicity increase
Solution Approach 1:
By creating capsid variants with localized mutations in specific variable regions, the patent achieves local quality enhancement where the capsid selectively targets cardiac tissue. This selective targeting ensures that therapeutic doses are concentrated in the heart rather than distributed systemically, reducing inflammation and toxicity while maintaining effective cardiac transduction
Solution Approach 2:
The patent creates engineered capsid variants that copy and adapt successful binding motifs from natural capsids. By incorporating conserved structural elements while introducing targeted mutations, the engineered capsids achieve efficient cardiac transduction at lower doses, avoiding the need for high systemic dosing that causes toxicity
3Ease of manufacture
If wild-type AAV9 capsid is used, then vector production is straightforward, but cardiac selectivity over liver is insufficient
Solution Approach 1:
The patent segments the capsid protein into functional domains, with specific focus on the variable regions (VR-IV, VR-V, VR-VII, VR-VIII) that determine tissue tropism. By independently modifying these segmented regions while maintaining the overall capsid structure, the patent achieves cardiac selectivity without compromising capsid functionality or production feasibility
Solution Approach 2:
The patent applies local quality by making targeted modifications to specific segments of the capsid protein sequence. These localized changes in variable regions alter tissue specificity while leaving the rest of the capsid structure intact, ensuring that production processes remain straightforward while achieving improved cardiac selectivity
Data Source
AI summary
The present disclosure provides recombinant adeno-associated virus (rAAV) virions with an engineered capsid protein. In particular, the disclosure provides AAV9 virions with engineered AAV9 capsid, AAV5/9 chimeric capsid or combinatory capsid that achieves increased transduction efficiency in cardiac cells, increased cell-type selectivity, and/or other desirable properties.