Replication-Deficient Adenovirus via Mutated DNA-Binding Protein
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Solution Overview
Problem
Current antiviral therapies and vaccines are ineffective against severe adenoviral infections, and there is a need for attenuated adenoviruses that can be used for vaccine development and gene therapy, requiring a high safety level for human use.
Innovation Solution
A modified adenovirus with a mutated DNA-binding protein (DBP) that inhibits adenoviral DNA replication, preventing the production of virus progeny, is developed. This mutation disrupts the ability of the virus to replicate by altering specific amino acid sequences within the DBP, specifically the NH2-Ser-[Gly/Ser/Ala]-[Lys/Arg]-Ser-COOH motif, which is crucial for DNA replication.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a wild-type adenovirus is used, then high viral replication and progeny production occur, but safety is compromised for therapeutic use
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues (Ser354, Ser76) in the DBP protein sequence, altering the biochemical parameters of the virus to achieve replication deficiency. This mutation changes the DNA-binding properties of DBP, thereby inhibiting viral DNA replication while maintaining viral entry and expression capabilities, resolving the contradiction between safety and replication productivity.
2Reliability
If antiviral therapies are developed, then treatment options improve, but effectiveness against severe adenoviral infections remains insufficient
Solution Approach 1:
The patent converts the harmful replication capability of wild-type adenoviruses into a beneficial feature by creating replication-deficient viruses through DBP mutation. The mutated DBP protein inadvertently provides therapeutic benefit by blocking viral replication while allowing controlled gene delivery, thus converting a potential harm (uncontrolled replication) into a benefit (safe gene therapy vector).
Solution Approach 2:
The patent extracts the replication function from the adenovirus by mutating the DBP protein, separating the gene delivery capability from the replication capability. This allows the virus to function as a safe delivery vehicle for therapeutic genes without the harmful side effect of uncontrolled viral replication, simplifying the therapeutic approach.
3Reliability
If vaccines are developed using attenuated adenoviruses, then protection against adenoviral infections improves, but the attenuation mechanism must be safe and effective
Solution Approach 1:
The patent applies local quality by introducing mutations at specific local positions (Ser354, Ser76) within the DBP protein sequence rather than globally attenuating the virus. This localized mutation approach provides precise control over the attenuation mechanism, ensuring safety while maintaining immunogenicity for vaccine development.
Data Source
AI summary
The present invention generally relates to the field of adenoviruses and adenoviral vectors that can be used as vaccines and gene therapy vectors. More specifically, the present invention relates to an adenovirus or an adenoviral vector that comprises a mutated DNA-binding protein that inhibits adenoviral DNA replication in a cell infected with a virus expressing said protein. The invention further relates to a nucleotide sequence encoding the mutated DNA-binding protein. In another aspect, the invention provides pharmaceutical compositions, vaccines and cells that comprise the mutated protein, a nucleotide sequence encoding same, or a modified adenovirus or adenoviral vector comprising any of those. The invention also relates to the use of the mutated protein, a nucleotide sequence encoding the same, or an adenovirus or recombinant adenoviral vector comprising any of those for the preparation of a vaccine.