Engineered rAAV Capsids for Targeted Gene Therapy
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Solution Overview
Problem
Current recombinant adeno-associated virus (rAAV) gene therapies face challenges due to limited transduction of specific cell types and organs, off-target effects, and difficulty in crossing the blood-brain barrier, leading to reduced efficacy and specificity in therapeutic applications.
Innovation Solution
Engineering rAAVs with capsids that have specificity engineered into the capsid structure through iterative rounds of positive and negative selection, including 7-mer peptide substitutions at specific residues of the AAV9 capsid protein, to enhance tropism for target tissues and reduce off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Area of stationary object
If intravenous administration is used to achieve broad access to tissues and organs, then delivery coverage is improved, but off-target effects increase due to transduction of unimpacted organs and cell types
Solution Approach 1:
The patent applies local quality by engineering specific amino acid substitutions in the AAV capsid protein sequence to create variants with tissue-specific tropism. These localized modifications at specific capsid regions enable the virus to selectively transduce target tissues while avoiding off-target organs, thus maintaining broad delivery coverage through intravenous administration while reducing harmful off-target effects.
2Productivity
If larger viral load is used to achieve sufficient therapeutic levels in target tissue, then transduction efficiency is improved, but off-target transduction increases
Solution Approach 1:
The patent applies parameter changes by modifying the capsid protein's amino acid sequence to alter its biological properties. Specifically, substitutions at positions such as 452-458 of AAV9 VP1 change the capsid's tropism parameters, enabling high-affinity binding to target tissue receptors while having low affinity for off-target organs. This allows achieving sufficient therapeutic transduction levels without requiring larger viral loads that would cause off-target transduction.
3Area of stationary object
If current rAAV serotypes are used for systemic delivery, then broad distribution is achieved, but specificity to cross the blood brain barrier is limited
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions in the capsid protein that create localized binding interfaces for crossing the blood-brain barrier. These targeted modifications at specific capsid regions enable the virus to selectively interact with BBB transport mechanisms while maintaining broad systemic distribution capabilities through intravenous or intranasal administration routes.
Data Source
AI summary
Described herein are compositions and kits comprising recombinant adeno-associated viruses (rAAVs) with tropisms showing increased specificity and efficiency of viral transduction in targeted cell-types, for e.g., the brain, and lung. The rAAV compositions described herein also have tropisms showing decreased specificity and decreased efficiency of viral transduction in an off-target cell type, for e.g., the liver. The rAAV compositions described herein encapsidate a transgene, such a therapeutic nucleic acid. Upon systemic delivery to a subject, the rAAV is capable of increased specificity and increased transduction of the transgene in a target cell-type, as compared to a parental or reference AAV.