Directed-Evolution rAAV Capsids for Brain and Heart Enrichment
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Solution Overview
Problem
Existing recombinant adeno-associated viruses (rAAVs) do not efficiently target and transduce brain and heart tissues upon systemic delivery, limiting their effectiveness in treating related diseases.
Innovation Solution
Engineering rAAVs with peptide insertions and substitutions in the capsid structure through directed evolution in non-human primates, resulting in variants with enhanced transduction enrichment in brain and heart tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If unmodified rAAVs such as AAV9 are used for systemic delivery, then the virus can be easily administered, but the tissue enrichment in brain and heart is insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the capsid protein sequence of AAV9 through directed evolution in non-human primates. Specific amino acid residues were mutated to alter capsid properties, enabling the virus to achieve both easy systemic delivery and enhanced tissue enrichment in brain and heart, resolving the contradiction between administration ease and targeting reliability
Solution Approach 2:
The patent employs feedback mechanisms through iterative selection rounds in non-human primates. The capsid variants were continuously selected and refined based on observed transduction efficiency and tissue enrichment data, allowing the system to learn from previous generations and progressively improve both deliverability and targeting accuracy
2Reliability
If existing AAV serotypes are used, then the vector has low immunogenicity and long-term persistence, but the transduction efficiency in brain and heart is limited
Solution Approach 1:
The patent applies local quality by making targeted modifications to specific regions of the capsid protein while maintaining the overall structure and properties that confer low immunogenicity and long-term persistence. The mutations were localized to specific amino acid positions that influence transduction efficiency without compromising the fundamental safety characteristics of the AAV vector
Solution Approach 2:
The patent utilizes parameter changes by carefully adjusting capsid protein parameters (amino acid sequences) to enhance transduction efficiency in brain and heart while preserving the inherent safety profile of AAV. The directed evolution process optimized productivity parameters without sacrificing the reliability attributes of persistence and low immunogenicity
Data Source
AI summary
Described herein are compositions and kits comprising recombinant adeno-associated viruses (rAAVs) with increased transduction enrichment in the brain, heart, or brain and heart. 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 brain-related and heart-related diseases and conditions.