Adenovirus Penton Mutations Reduce Inflammation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current adenovirus vectors for gene therapy face challenges in triggering severe inflammatory responses and toxicity upon intravascular administration, limiting their safety and efficacy for clinical use due to interactions with host cells and immune systems.
Innovation Solution
Development of novel adenovirus vectors with mutations in the penton base protein that ablate interactions with cellular β3-integrins, allowing for reduced inflammation and enhanced targeting of specific cells and tissues, including tumor cells, through modifications such as deletion or substitution of the RGD motif with iso-functional amino acid sequences.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If adenovirus vectors use wild-type penton base protein with RGD motif for efficient cell internalization, then gene transfer efficiency is improved, but severe inflammatory response and toxicity occur upon intravascular administration
Solution Approach 1:
The patent extracts and removes the RGD motif from the penton base protein of adenovirus vectors. This deletion eliminates the harmful interaction with β3-integrins that triggers inflammatory responses in macrophages, while the virus retains alternative mechanisms for cell entry and gene transfer, thus resolving the contradiction between efficiency and safety
Solution Approach 2:
The patent modifies the amino acid sequence parameter of the penton base protein by deleting or mutating the RGD motif. This parameter change alters the virus's interaction profile with cellular integrins, reducing inflammatory activation while maintaining sufficient cell binding and internalization capabilities for effective gene delivery
2Productivity
If adenovirus vectors interact with β3-integrins via RGD motif for efficient internalization, then transduction efficacy is improved, but systemic toxicity increases
Solution Approach 1:
The patent extracts the RGD motif from the penton base protein, removing the specific interaction mechanism that causes systemic toxicity through macrophage activation. The virus maintains transduction efficacy through alternative cell entry pathways that do not engage β3-integrins, thus eliminating harmful systemic effects while preserving therapeutic function
3Reliability
If adenovirus vectors use wild-type penton base for broad cell targeting, then infectivity is improved, but selectivity for specific tissues is reduced
Solution Approach 1:
The patent applies local quality modification by altering the penton base protein's interaction properties specifically for in vivo applications. The mutated penton base maintains sufficient binding capability for hepatocyte infection while eliminating non-specific binding to macrophages and other cell types, thereby achieving tissue selectivity without sacrificing overall infectivity
Data Source
AI summary
The present invention describes generation and the use of adenovirus variants (Ad) possessing modified capsid penton base protein where mutations in the penton based RGD loop are made to avoid Ad binding to cellular β3-integrins. Specifically, the ablation of Ad penton base interaction with cellular β3-integrins results in reduced activation of inflammation after intravenous Ad administration. Further, the introduction into penton RGD loop of non-RGD containing peptides, which mediate virus entry into the cell via new cellular receptors, allows for the efficient Ad-mediated gene delivery into target cells in vivo after intravascular virus administration and triggers significantly reduced toxicity associated with Ad injection.