Modified AAV Capsid Proteins for Targeted Gene Delivery
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Solution Overview
Problem
Current adeno-associated virus (AAV) vectors lack efficient targeting capabilities for specific tissues, particularly for neuronal cells and cardiac tissue, and exhibit undesired transduction in peripheral organs like the liver, spleen, and kidney.
Innovation Solution
Modified AAV capsid proteins with specific amino acid modifications, such as substitutions and insertions at residues like S262, A263, S264, T265, A267, and H272, enable selective transduction of neuronal cells and cardiac tissue while detargeting peripheral organs by altering the capsid's tropism and transduction profile.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current AAV vectors are used for gene transfer, then they can deliver genetic material to tissues, but they lack efficient targeting capabilities for specific tissues and exhibit undesired transduction in peripheral organs
Solution Approach 1:
The patent applies local quality by making specific amino acid substitutions at targeted positions (S262, A263, S264, T265, A267, H272) in the AAV capsid protein sequence. These localized modifications alter the capsid's interaction properties with specific tissue receptors, enabling selective transduction of neuronal and cardiac tissues while reducing uptake in peripheral organs like liver, spleen, and kidney.
Solution Approach 2:
The patent changes the biochemical parameters of the AAV capsid by introducing amino acid substitutions and insertions that modify the capsid's surface properties, charge distribution, and receptor binding characteristics. These parameter changes fundamentally alter the tropism profile of the vector, shifting preference from non-specific to specific tissue targeting.
2Productivity
If AAV vectors are modified with multiple amino acid substitutions and insertions, then transduction efficiency in target tissues improves, but the complexity of vector design and manufacturing increases
Solution Approach 1:
The patent segments the capsid modification approach by identifying and modifying specific functional domains or regions within the capsid protein sequence. Rather than random mutations, the substitutions are concentrated at particular positions (S262, A263, S264, T265, A267, H272) that are critical for tissue-specific recognition, allowing systematic optimization of targeting while maintaining manufacturing feasibility.
Solution Approach 2:
The patent creates a composite capsid structure by combining wild-type AAV sequence elements with engineered mutant elements at specific positions. This composite approach allows the vector to retain essential functions of the parent AAV while incorporating new properties for enhanced tissue specificity, balancing improved performance with manageable complexity.
Data Source
AI summary
The present disclosure provides AAV capsid proteins comprising a modification in the amino acid sequence and virus capsids and virus vectors comprising the modified AAV capsid protein. The disclosure also provides methods of administering the virus vectors and virus capsids of the disclosure to a cell or to a subject in vivo.