Engineered AAV Capsid Peptide Insertions for Brain Enrichment
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Solution Overview
Problem
Existing recombinant adeno-associated viruses (rAAVs) face challenges in selectively and efficiently expressing in the central nervous system (CNS) upon systemic delivery, necessitating improved transduction enrichment.
Innovation Solution
Engineering rAAVs with peptide insertions in the capsid structure through iterative selection in non-human primates, resulting in variants with enhanced transduction enrichment in the CNS, utilizing specific amino-acid sequences for targeted expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If existing AAV serotypes are used for systemic delivery, then they can deliver to various tissues, but they fail to achieve selective and efficient expression in the central nervous system
Solution Approach 1:
The patent applies local quality by introducing specific peptide insertions at defined positions within the AAV capsid structure. These localized modifications (e.g., insertions at positions 588-589, 452-458, or 640-645) alter the properties of specific regions of the capsid to enhance CNS targeting while preserving overall capsid function and systemic delivery capability.
Solution Approach 2:
The patent employs parameter changes by systematically varying capsid amino acid sequences through multiple peptide insertions and substitutions. The iterative selection process in NHPs identifies optimal sequence parameters that maximize CNS transduction efficiency, resulting in variants with enhanced specific binding or entry characteristics for CNS cells.
2Reliability
If peptide insertions are engineered into the capsid structure, then CNS transduction enrichment is improved, but the capsid structure complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the capsid modification into multiple independent peptide insertion sites (e.g., positions 588-589, 452-458, 640-645). Each insertion is a discrete, modular element that can be independently designed, tested, and optimized, simplifying the overall engineering process despite the cumulative complexity.
Solution Approach 2:
The patent achieves universality by designing peptide insertions that serve multiple functions: they enhance CNS targeting specificity, maintain capsid assembly efficiency, and preserve transgene packaging capability. The selected peptide sequences are optimized to fulfill several functional requirements simultaneously, reducing the need for additional complex modifications.
3Reliability
If iterative selection in non-human primates is performed, then transduction enrichment in CNS is enhanced, but the time and resources required for development increase
Solution Approach 1:
The patent applies preliminary action by conducting iterative selections in non-human primates during the development phase to pre-optimize capsid variants for human CNS transduction. This preliminary testing in a physiologically relevant model identifies high-performance variants before clinical application, reducing the need for further extensive optimization and accelerating translational timelines.
Solution Approach 2:
The patent employs feedback through the iterative selection process where transduction outcomes in NHPs are measured and used to guide subsequent rounds of capsid variant generation. This feedback loop continuously refines the capsid sequences, converging on optimal variants that achieve high CNS transduction enrichment while minimizing the number of iterations required.
Data Source
AI summary
Described herein are compositions and kits comprising recombinant adeno-associated viruses (rAAVs) with increased viral transduction enrichment in the CNS. The rAAV compositions described herein encapsidate a transgene, such as a therapeutic nucleic acid. Gene therapy using the rAAVs is described. Also described are methods of treating CNS-related diseases and conditions.