Monkey Adenovirus Vector Propagation Using Human E1 E4 Genes
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The use of adenoviral vectors for gene transfer is limited by pre-existing immunity in humans, which prevents repeated administration and efficient transgene expression due to neutralization by antibodies, and there is a host range restriction that hinders monkey adenoviruses from replicating efficiently on human cells.
Innovation Solution
Incorporating human adenovirus gene products, specifically the E1 and E4 regions, into monkey adenoviruses to overcome the host range restriction and pre-existing immunity, allowing for efficient propagation and replication on human cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If human adenovirus gene products (E1 and E4 regions) are incorporated into monkey adenoviruses, then replication efficiency on human cells is improved, but device complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the human adenovirus genome into specific functional regions (E1 and E4 regions) and incorporating only these essential segments into the monkey adenovirus vector. This selective incorporation provides the necessary replication functions on human cells while avoiding the addition of entire complex genomic sequences, thus balancing improved replication efficiency with controlled vector complexity.
Solution Approach 2:
The patent achieves universality by engineering the monkey adenovirus to function across species barriers. The incorporated human adenovirus E1 and E4 gene products enable the vector to replicate efficiently on both monkey and human cells, creating a multi-host capable vector system that overcomes host range restrictions while maintaining a relatively streamlined structure compared to fully human adenoviral vectors.
2Reliability
If monkey adenoviruses are used for gene transfer, then pre-existing immunity is avoided, but host range restriction prevents efficient replication on human cells
Solution Approach 1:
The patent applies local quality by making specific modifications to particular regions of the monkey adenovirus genome (incorporating human E1 and E4 regions) while leaving other regions unchanged. This localized genetic modification approach confers the specific ability to replicate on human cells without altering the overall monkey adenovirus identity and immune evasion properties, thus maintaining reliability while improving productivity.
Solution Approach 2:
The patent creates a composite viral vector by combining genetic elements from two different adenovirus species. The resulting hybrid vector contains monkey adenovirus structural components (providing immune avoidance) combined with human adenovirus replication genes (E1 and E4 regions), enabling efficient replication on human cells. This composite approach resolves the contradiction between species-specific immunity avoidance and cross-species replication capability.
Data Source
AI summary
The invention provides methods for propagating a monkey adenovirus in a cell, including a human cell, comprising one or more gene products isolated from a human adenovirus. Also provided are methods for propagating wherein the monkey adenovirus comprises a nucleic acid sequence encoding a human adenovirus gene product. The invention further provides a monkey adenovirus, including a replication-deficient monkey adenovirus, obtained by such propagation methods.