Engineered AAV Capsids for Targeted Non-Liver Gene Delivery
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Solution Overview
Problem
Conventional recombinant adeno-associated viruses (rAAVs) exhibit limited cell tropism, requiring high doses for effective delivery to non-liver tissues, leading to liver toxicity and manufacturing challenges, and species-specific transduction efficiency varies, making preclinical mouse studies inaccurate for human applications.
Innovation Solution
Engineered AAV capsids with cell-specific tropism and reduced immunogenicity, encoded by engineered AAV capsid polynucleotides, are developed to enhance targeted delivery to specific cell types and tissues, using methods that include expressing these capsids in cells and selecting high-titer variants.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional rAAVs with natural capsid variants are used for gene delivery to non-liver tissues, then the delivery vehicle is simple and well-established, but transduction efficiency is limited and high doses are required leading to liver toxicity
Solution Approach 1:
The patent applies local quality by engineering specific regions of the AAV capsid protein with targeted amino acid substitutions and insertions. These localized modifications at specific capsid positions alter the virus's tissue tropism and cellular uptake properties, enabling selective targeting of non-liver tissues while avoiding systemic liver toxicity associated with high-dose conventional rAAV administration
Solution Approach 2:
The patent implements parameter changes by systematically modifying capsid protein sequences through amino acid substitutions, deletions, and insertions. These sequence parameter changes result in altered capsid structures that confer enhanced transduction efficiency for specific non-liver cell types and tissues, while reducing off-target liver accumulation and toxicity
2Reliability
If high doses of conventional rAAV are administered to achieve effective transduction in non-liver tissues, then transduction efficiency improves, but liver toxicity increases and manufacturing challenges arise
Solution Approach 1:
The patent applies local quality by engineering specific regions of the AAV capsid protein with targeted amino acid substitutions and insertions. These localized modifications at specific capsid positions alter the virus's tissue tropism and cellular uptake properties, enabling selective targeting of non-liver tissues while avoiding systemic liver toxicity associated with high-dose conventional rAAV administration
Solution Approach 2:
The patent converts the harmful liver tropism of conventional AAV into a benefit by engineering capsid variants with reversed or reduced liver targeting. The modified capsids specifically avoid liver uptake while maintaining or enhancing transduction of desired non-liver tissues, thereby eliminating toxicity without requiring dose reduction
3Ease of manufacture
If conventional rAAV capsids are used, then manufacturing processes are established, but manufacturing sufficient amounts for adult patients remains extremely challenging
Solution Approach 1:
The patent implements parameter changes by systematically modifying capsid protein sequences through amino acid substitutions, deletions, and insertions. These sequence parameter changes result in altered capsid structures that confer enhanced transduction efficiency for specific non-liver cell types and tissues, while reducing off-target liver accumulation and toxicity
4Ease of operation
If preclinical studies use mouse models with conventional rAAV, then animal studies are feasible and standardized, but results do not accurately reflect human responses due to species differences
Solution Approach 1:
The patent applies universality by developing capsid variants that achieve consistent transduction performance across multiple species including mice, primates, and humans. The engineered capsids display reduced species-specific variability in cellular uptake and transduction efficiency, enabling preclinical mouse studies to more accurately predict human clinical outcomes
Data Source
AI summary
Described herein are methods of generating engineered viral capsid variants. Also described herein are engineered viral capsid variants, engineered viral particles and formulations and cells thereof. Also described herein are vector systems containing an engineered viral capsid polynucleotide and uses thereof.