Herpesvirus Vector Transgene Codon Optimization
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Solution Overview
Problem
Current herpesvirus vector systems for gene therapy and vaccine development face limitations in effectively expressing nucleic acid sequences and inducing an immune response, particularly in regulating the temporal expression of transgenes as late gene products.
Innovation Solution
The development of replication-competent herpesvirus vectors with transgenes modified to have a codon usage signature of herpesvirus late genes, allowing for enhanced immune response and expression by aligning codons with those of herpesvirus late genes, such as glycoproteins, to mimic the natural expression patterns of herpesviruses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If transgenes are expressed using conventional promoters in herpesvirus vectors, then transgene expression is achieved, but temporal regulation of expression as late gene products is insufficient
Solution Approach 1:
The patent changes the codon usage parameters of the transgene to match the codon usage signature of herpesvirus late genes. This parameter change enables the transgene to be recognized and expressed temporally as a late gene product, resolving the contradiction between temporal regulation and expression efficiency
Solution Approach 2:
The patent copies the codon usage signature pattern from native herpesvirus late genes and applies it to the heterologous transgene. By copying this regulatory signature, the transgene inherits the temporal expression characteristics of late genes without requiring modification of viral promoters or regulatory elements
2Quantity of substance
If transgenes are modified to have codon usage signature of herpesvirus late genes, then immune response is enhanced, but complexity of transgene construction increases
Solution Approach 1:
The patent applies codon optimization by changing the nucleotide sequence parameters of the transgene while preserving the amino acid sequence. This parameter change enhances immune response by mimicking viral late gene expression patterns, and the process uses automated tools to minimize construction complexity
Solution Approach 2:
The patent replaces complex regulatory element engineering with a simpler codon substitution approach. Instead of modifying promoters, enhancers, or other regulatory sequences, the invention uses computational codon optimization to achieve the same regulatory effect, reducing construction complexity while enhancing immune response
Data Source
AI summary
Compositions are provided comprising a replication-competent herpesvirus vector system and/or a herpesvirus vector particle comprising a heterologous recombinant transgene of interest encoding an antigen of interest (e.g., a tumor-associated antigen, a microbial antigen, etc.), wherein the recombinant transgene has been modified to comprise a codon usage signature of a herpesvirus late gene operably linked to an active promoter. Such compositions find use in a variety of methods including, for example, methods of generating an immune response against an antigen of interest in a subject in need thereof, as well as methods for treating or preventing cancer or a microbial infection.