CpG-Modified AAV Vectors for Reduced Innate Immune Responses
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Solution Overview
Problem
Current AAV-mediated gene therapy approaches face challenges due to innate immune responses, particularly activation of the TLR9-MyD88 pathway, which can limit the effectiveness of gene delivery by inducing immune reactions against the vector and transgene.
Innovation Solution
Development of CpG-modified AAV vectors with reduced or depleted CpG dinucleotides in their nucleic acid sequences, packaged within an AAV capsid, to minimize immune responses by reducing CpG di-nucleotides in the vector's nucleic acid sequences, including inverted terminal repeats and exogenous gene sequences, thereby reducing immune activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AAV vectors with standard nucleic acid sequences are used for gene delivery, then the vector can deliver the transgene effectively, but the vector activates the TLR9-MyD88 innate immune pathway causing immune responses that compromise gene therapy outcomes
Solution Approach 1:
The patent applies parameter changes by modifying the nucleic acid sequence composition of the AAV vector, specifically reducing or depleting CpG dinucleotides in the inverted terminal repeats and exogenous gene sequences. This chemical composition change in the nucleic acid prevents TLR9 recognition and subsequent MyD88 pathway activation, thereby reducing innate immune responses while maintaining gene delivery effectiveness
2Duration of action of stationary object
If CpG-modified AAV vectors with reduced CpG dinucleotides are used, then immune responses are reduced allowing stable long-term gene expression, but the nucleic acid sequence must be modified which increases vector construction complexity
Solution Approach 1:
The patent modifies nucleic acid sequence parameters by systematically reducing or depleting CpG dinucleotides in specific regions (inverted terminal repeats and exogenous gene sequences) during vector construction. This sequence composition modification enables long-term stable transgene expression by preventing immune-mediated vector clearance, while the modification process itself integrates into standard vector construction workflows
Data Source
AI summary
A CpG-modified recombinant adeno-associated viral (AAV) vector is described. The vector carries a nucleic acid molecule comprising AAV inverted terminal repeat (ITR) sequences and an exogenous gene sequence under the control of regulatory sequences which control expression of the gene product, in which the nucleic acid sequences carried by the vector are modified to significantly reduce CpG di-nucleotides such that an immune response to the vector is reduced as compared to the unmodified AAV vector. Also provided are methods and regimens for delivering transgenes using these AAV viral vectors, in which the innate immune response to the vector and/or transgene is significantly modulated.