Adenosome Vesicles for Large-DNA Tumor Delivery
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Solution Overview
Problem
Existing adenovirus vectors face challenges in efficient delivery to metastasized tumors due to their large size, 'stickiness' to cells, inability to transfer via blood, neutralization by antibodies, and binding to/uptake in non-target cells, leading to cytotoxicity and immunogenic responses, while extracellular vesicles offer potential as therapeutic vehicles but lack reliable methods for loading large DNA constructs.
Innovation Solution
Development of adenosomes, which are cellular vesicles loaded with adenoviral core proteins V and VII under heterologous promoter control, allowing efficient packaging and delivery of adenoviral nucleic acid, including mutations in early genes and deletions of capsid proteins to enhance therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If adenovirus vectors are used for gene delivery, then the ability to infect both replicating and quiescent cells is improved, but the large size and stickiness to cells worsen delivery efficiency to metastasized tumors
Solution Approach 1:
The patent segments the adenovirus structure by separating the viral genome and core proteins from the capsid proteins. The adenosome contains only the essential viral components (genome, protein V, protein VII) without the bulky capsid structure, thereby reducing size while preserving infection capability through the retained fiber and penton base proteins.
Solution Approach 2:
The patent extracts and removes the capsid proteins (hexon, penton, fiber) from the adenovirus structure, leaving only the essential core components. This extraction eliminates the 'stickiness' and size issues while maintaining the ability to deliver genetic material to target cells.
2Quantity of substance
If adenovirus vectors are used, then large pieces of DNA can be hosted, but the inability to transfer via blood and neutralization by antibodies worsen delivery to metastasized tumors
Solution Approach 1:
The patent uses cellular vesicles as an intermediary carrier to replace the traditional adenovirus capsid. These vesicles provide a protective environment for the viral genome and core proteins, enabling transfer via blood circulation and protecting against antibody neutralization while maintaining DNA hosting capacity.
Solution Approach 2:
The patent creates a simplified copy of the adenovirus system that retains only the essential functional elements (genome, core proteins) without the problematic outer structure. This minimal viable version preserves DNA capacity while eliminating immunogenicity and improving circulation stability.
3Adaptability or versatility
If adenovirus vectors are used, then gene therapy capability is achieved, but binding to and uptake in non-target cells leading to cytotoxicity worsens therapeutic safety
Solution Approach 1:
The patent applies local quality by concentrating the therapeutic function in specific localized components (viral genome and core proteins) while removing the non-essential capsid proteins that cause off-target binding. This localization ensures gene therapy capability is maintained while reducing harmful interactions with non-target cells.
Solution Approach 2:
The patent converts the harmful effect of capsid proteins (which cause stickiness and off-target binding) into a benefit by completely removing them. The resulting adenosome structure eliminates cytotoxicity while preserving the essential gene delivery function through the retained core components.
Data Source
AI summary
The invention relates to a recombinant adenovirus nucleic acid wherein the gene encoding protein V and/or the gene encoding protein VII is placed under control of a heterologous promoter, to a recombinant adenovirus nucleic acid wherein the adenoviral nucleotide sequence is mutated in such a way that it is no longer capable of producing one or more of the coat proteins, to cellular vesicles filled with such adenoviral material, cells provided with such adenoviral material and to methods and use thereof.