Engineered AAV Capsid Targeting Cardiac Muscle
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Solution Overview
Problem
Recombinant adeno-associated viruses (rAAVs) with natural capsid variants have limited cell tropism, leading to inefficient delivery to non-liver cells and tissues, such as the central nervous system, requiring high doses that often result in liver toxicity and manufacturing challenges, with species-specific responses differing between mouse and primate models.
Innovation Solution
Engineered AAV capsid proteins with specific n-mer inserts or RGD motifs are incorporated into AAV proteins to enhance targeting specificity to cardiac muscle cells, reducing uptake in non-cardiac muscle cells like liver cells, and incorporating mutations at specific positions to improve transduction efficiency and species specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional rAAVs with natural capsid variants are used for systemic delivery, then liver transduction is achieved, but transduction efficiency in non-liver cells and tissues is limited
Solution Approach 1:
The patent applies local quality by engineering specific regions of the AAV capsid protein with targeted mutations at defined positions (e.g., positions 267, 269, 504, 505, 590) to create cardiac muscle-specific recognition properties while maintaining overall capsid structure and function
Solution Approach 2:
The patent changes the physical-chemical parameters of the capsid protein by introducing specific amino acid substitutions at defined positions, which alters the capsid's interaction properties with cardiac muscle cell receptors to enhance transduction efficiency
2Reliability
If large doses of conventional rAAV are administered to achieve transduction in non-liver tissues, then transduction efficiency improves, but liver toxicity occurs
Solution Approach 1:
The patent introduces cardiac muscle-specific targeting properties through localized mutations in the capsid protein, enabling selective transduction of cardiac cells at lower doses and reducing off-target effects in the liver
Solution Approach 2:
The patent converts the natural liver tropism of conventional AAV into a benefit by using it as a baseline and then introducing specific mutations that redirect specificity to cardiac muscle, thereby eliminating liver toxicity while maintaining transduction efficiency
3Ease of manufacture
If conventional rAAV is used for gene delivery, then manufacturing is simplified, but manufacturing sufficient amounts for adult patients is extremely challenging
Solution Approach 1:
The patent optimizes manufacturing by making precise parameter changes to the capsid gene sequence (specific mutations at defined positions) that enhance viral production efficiency and stability without requiring complex manufacturing process changes
4Productivity
If preclinical studies in mice are conducted, then initial testing is completed, but results do not accurately reflect outcomes in primates and humans
Solution Approach 1:
The patent creates capsid variants with universal applicability across species by introducing mutations that confer primate-specific or broad-spectrum cardiac muscle recognition, enabling preclinical mouse studies to more accurately predict human outcomes
Data Source
AI summary
Described in several exemplary embodiments are compositions including a targeting moiety effective to target a central nervous system cell and formulations thereof. In certain embodiments, the targeting moiety is composed of one or more n-mer inserts, that can include one or more RGD motifs, and/or one or more P-motifs. Also described in certain example embodiments are vector systems configured to generate polypeptides containing the one or more targeting moieties. Also described herein are methods of generating a targeting moiety effective to target a central nervous system cell and using the compositions containing the targeting moieties described herein, such as to deliver a cargo to a subject and/or treat a central nervous system disease, disorder, or system thereof.