Modified AAV Capsid Virions for Macrophage Gene Delivery
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current adeno-associated virus (AAV) vectors exhibit low infectivity in targeting macrophages, particularly microglia cells, limiting their effectiveness in gene delivery and therapeutic applications.
Innovation Solution
Development of recombinant AAV virions with variant capsid proteins that enhance infectivity in macrophages by modifying specific amino acid sequences, combined with heterologous nucleic acids encoding gene products for targeted gene delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type AAV capsid proteins are used, then the viral vector maintains natural biological properties and low immunogenicity, but infectivity in macrophages and microglia cells is low
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the AAV capsid protein sequence (e.g., positions 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100). These sequence variations create capsid proteins with altered properties that enhance infectivity for macrophages and microglia cells while maintaining the safety profile of AAV vectors.
Solution Approach 2:
The patent applies local quality by making specific localized modifications to the capsid protein sequence at particular amino acid positions rather than changing the entire sequence. This allows targeted optimization of cell-type specificity and infectivity for macrophages and microglia while preserving other important functions of the wild-type capsid.
2Productivity
If capsid protein sequence is modified to enhance infectivity, then gene delivery efficiency to macrophages improves, but deviation from wild-type structure increases
Solution Approach 1:
The patent systematically explores parameter changes in the capsid protein sequence by testing multiple variants with different amino acid substitutions at specific positions. This allows identification of optimal sequence modifications that maximize gene delivery efficiency to macrophages while maintaining adequate structural stability and safety.
Solution Approach 2:
The patent employs a screening approach where multiple capsid variants are generated and tested, with suboptimal variants being discarded and promising variants being recovered for further development. This iterative process allows identification of the best balance between enhanced infectivity and maintained structural fidelity.
Data Source
AI summary
The present disclosure provides recombinant adeno-associated virus (rAAV) virions comprising a variant AAV capsid protein. An rAAV virion of the present disclosure can exhibit greater infectivity of a macrophage. The present disclosure also provides methods of delivering a gene product to a target macrophage in an individual by administering to the individual an rAAV of the present disclosure. The present disclosure also provides treatment methods comprising administering to an individual in need thereof an rAAV virion of the present disclosure.