Engineered AAV Capsid Motifs for Cardiac-Selective Gene Delivery
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Solution Overview
Problem
Existing AAV9 vectors face challenges in achieving efficient and selective transduction of cardiac tissues while minimizing liver transduction, leading to systemic inflammation and toxicity due to high doses required for therapeutic levels.
Innovation Solution
Engineered AAV capsid proteins with specific amino acid substitutions and non-naturally occurring motifs, particularly at positions S586, A587, Q588, A589, and Q590, enhance cardiac tropism and selectivity, allowing for improved transduction efficiency and reduced liver trafficking.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AAV9 is used to deliver gene products to cardiac tissues, then transduction of the heart is achieved, but the majority of vector traffics to the liver causing systemic inflammation and toxicity
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at defined positions (S586, A587, Q588, A589, Q590) in the AAV9 capsid protein sequence. These localized modifications at the VR-VIII site alter the capsid's interaction properties with cardiac versus liver tissues, enhancing cardiac tropism while reducing liver uptake without changing the overall capsid structure or requiring high systemic doses.
2Reliability
If high systemic doses are administered to achieve therapeutic levels of cardiac transduction, then cardiac transduction efficiency is improved, but systemic inflammation and toxicity increase
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid composition at specific positions in the capsid protein (S586, A587, Q588, A589, Q590). These parameter modifications alter the capsid's biological properties, specifically its tissue selectivity, enabling therapeutic cardiac transduction at lower systemic doses and thereby reducing systemic inflammation and toxicity associated with high-dose administration.
3Adaptability or versatility
If AAV9 capsid protein is used with wild-type sequence, then general transduction capability is maintained, but cardiac selectivity is insufficient
Solution Approach 1:
The patent maintains general transduction capability while enhancing cardiac selectivity through localized amino acid substitutions at the VR-VIII site (positions S586, A587, Q588, A589, Q590). These targeted modifications preserve the capsid's overall function for gene delivery while specifically improving its affinity for cardiac tissues, achieving both adaptability and reliability.
Data Source
AI summary
In some aspects, the present disclosure provides engineered adeno-associated virus (AAV) capsid proteins comprising a non-naturally occurring amino acid motif described herein. In some embodiments, the present disclosure provides an AAV9, AAV5, AAVrh.10 or AAVrh.74-based engineered capsid protein, that when assembled into virions, achieves increased transduction efficiency of the heart, and/or other desirable properties. Also provided herein are recombinant AAV virions comprising any of the engineered capsid proteins described herein and uses thereof.