Modified Reovirus Sequences for Enhanced Infectivity and Reduced Toxicity
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Solution Overview
Problem
Current reoviruses lack effective modifications to enhance their replicative and infective capabilities, particularly in human cells, and their immunogenicity and toxicity pose challenges for therapeutic applications.
Innovation Solution
Development of reoviruses with modified nucleic acid and polypeptide sequences, including specific amino acid changes in proteins like lambda-3, sigma-3, mu-1, and mu-2, and nucleic acid modifications in genome segments, which increase replicative efficiency, reduce immunogenicity, and enhance ability to infect and kill cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If reoviruses are used for treating proliferative disorders, then therapeutic efficacy is improved, but immunogenicity and toxicity increase
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid sequences in reovirus proteins (lambda-3, sigma-3, mu-1, mu-2) to alter the virus's biological parameters. These sequence modifications reduce immunogenicity and toxicity while maintaining or enhancing therapeutic efficacy against proliferative disorders, directly resolving the contradiction between effectiveness and harmful effects.
Solution Approach 2:
The patent implements local quality by making targeted modifications to specific regions of the reovirus genome and proteins rather than complete redesign. Specific amino acid residues in key proteins are modified to locally optimize properties such as reduced immunogenicity in particular viral components while preserving overall viral function and therapeutic capability.
2Productivity
If reoviruses are modified to enhance replicative efficiency, then productivity is improved, but complexity of sequence modifications increases
Solution Approach 1:
The patent applies segmentation by dividing the reovirus genome into 10 discrete segments and focusing modifications on specific segments (L1, S4, M1, M2) that encode critical proteins for replication. This segmented approach allows targeted enhancement of replicative efficiency in specific viral components without requiring complex modifications across the entire genome, thus improving productivity while managing complexity.
Solution Approach 2:
The patent uses parameter changes to optimize replicative efficiency by modifying specific nucleic acid sequences and amino acid sequences in key proteins. These parameter modifications (nucleotide substitutions, amino acid changes) enhance viral replication without requiring complex structural redesign, thereby improving productivity with manageable modification complexity.
3Reliability
If reoviruses are modified to enhance infectivity, then effectiveness is improved, but difficulty of achieving and maintaining modifications increases
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid sequences in proteins lambda-3, sigma-3, mu-1, and mu-2 to enhance infectivity. These sequence parameter modifications improve the virus's ability to infect and kill cancer cells while maintaining stability through conserved structural regions, thus achieving enhanced infectivity without excessive difficulty in maintaining modifications.
Solution Approach 2:
The patent implements preliminary action by performing sequence modifications in the reovirus genome before viral assembly and replication. By pre-modifying the nucleic acid and protein sequences in the viral components, the patent ensures enhanced infectivity is built into the viral structure from the beginning, avoiding the need for complex post-infection modifications and reducing the difficulty of achieving and maintaining desired infectivity properties.
Data Source
AI summary
The invention provides for modified reovirus nucleic acid sequences and modified reovirus polypeptide sequences as well as reoviruses containing such modified nucleic acid or polypeptide sequences. The invention also provides for pharmaceutical compositions that include reoviruses having a modified sequence as well as methods of making and using such reoviruses.