AAV Capsid Peptide Insertion for T-Cell Transduction
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Solution Overview
Problem
Current adeno-associated virus (AAV) vectors have limited transduction efficiency into T-cells, which is a challenge for gene therapy applications, particularly in addressing T-cell exhaustion in chronic infections and cancer.
Innovation Solution
Development of recombinant AAV vectors incorporating transduction-associated peptides into the capsid proteins, specifically replacing or inserting amino acids at certain positions to enhance cellular transduction efficiency into T-cells, thereby improving the targeting and delivery of therapeutic nucleic acids.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If wild-type AAV vectors are used, then the vectors maintain natural capsid structure and low immunogenicity, but transduction efficiency into T-cells is limited
Solution Approach 1:
The patent applies local quality by making specific point mutations at defined positions (e.g., positions 454-460) in the AAV6 capsid protein sequence while leaving the rest of the capsid structure intact. This localized modification approach allows enhancement of T-cell transduction efficiency through specific peptide substitutions (such as replacing amino acids with those in SEQ ID NOs: 17-23) without altering the overall capsid architecture that confers low immunogenicity and stable structure.
2Productivity
If capsid protein sequence is modified to enhance transduction, then transduction efficiency improves, but structural stability may be compromised
Solution Approach 1:
The patent employs parameter changes by systematically varying amino acid residues at specific positions (454-460) in the capsid protein sequence to optimize transduction efficiency. Multiple variant sequences (SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14) are generated with different amino acid compositions at these positions, allowing selection of variants that achieve high transduction efficiency while maintaining capsid structural integrity through controlled parameter modification rather than extensive sequence changes.
Data Source
AI summary
The disclosure provides variant AAV capsid proteins and AAV capsids and virus vectors comprising the same. The virus vectors described herein may have increased transduction in a target cell of interest, such as a T-cell, compared to native AAV capsid sequences. The disclosure also provides methods of administering the virus vectors and virus capsids of the disclosure to a cell or to a patient in need thereof.