Adenovirus Vectors with Modified Penton Base for Targeted Transduction
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Solution Overview
Problem
Current adenovirus vectors for gene therapy and cancer therapy face challenges in achieving targeted cell-type-specific gene delivery while minimizing vector-associated toxicities, due to non-specific receptor binding and activation of the innate immune system.
Innovation Solution
Development of adenovirus vectors with modified capsids, specifically mutated penton base proteins lacking the RGD motif and incorporating peptides that interact with non-RGD-binding integrin classes, combined with fiber proteins targeting CD46 or DSG2 receptors, to enhance receptor selectivity and reduce immune activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adenovirus vectors use native fiber and penton proteins for cell attachment and internalization, then gene delivery efficiency is maintained, but receptor binding becomes non-specific and immune system activation occurs causing toxicity
Solution Approach 1:
The patent removes the RGD motif from the penton base protein, extracting the harmful binding function that causes non-specific cell attachment and immune activation. This deletion eliminates the interaction with integrin receptors that mediate unwanted cellular uptake and inflammatory responses, while preserving the essential gene delivery function through alternative mechanisms.
Solution Approach 2:
The patent introduces specific peptide sequences into the penton base protein at defined locations to confer selective binding properties. These localized peptide insertions provide targeted interaction with specific cell surface receptors, enabling cell-type-specific gene delivery while maintaining structural integrity of the viral capsid and avoiding non-specific immune recognition.
2Adaptability or versatility
If adenovirus vectors are designed for broad cell type infectivity, then gene delivery versatility is improved, but selectivity for specific target cells is lost leading to off-target effects
Solution Approach 1:
The patent modifies the biochemical parameters of the penton base protein by altering amino acid sequences to change binding specificity. By changing the molecular recognition properties of the penton base through peptide insertions or substitutions, the vector achieves selective attachment to specific cell surface receptors, enabling precise targeting while maintaining efficient gene delivery to the intended cell types.
3Productivity
If RGD motif is present in penton base for integrin binding, then viral internalization efficiency is improved, but inflammatory cytokine production is activated causing toxicity
Solution Approach 1:
The patent converts the harmful RGD-integrin interaction into a beneficial selective targeting mechanism by designing peptide sequences that mimic certain integrin-binding properties while avoiding the inflammatory pathway activation. The modified penton base achieves efficient cellular internalization through alternative receptor interactions that do not trigger the harmful inflammatory cytokine response associated with native RGD binding.
Data Source
AI summary
The present application provides compositions and methods for increasing safety, selectivity, and efficacy of transduction of human cells, including human long-term repopulating and hematopoietic stem cells (LT-HSC) and human cancer cells, by adenovirus vectors through multiplexed targeting of virus attachment and internalization receptors. Multiplexing targeting Ad vector receptor specificities through the combination of i) restricting fiber-specific attachment receptors, ii) deleting the RGD amino acid motif from the penton base protein, and iii) inserting into Ad penton base protein of peptides that lack the RGD amino acid motif and enable vector interaction with integrin classes expressed on target cells, allows for the improvement of safety, selectivity, and efficacy of vector-mediated transduction of human cells in vitro and after intravenous vector administration in vivo.