Mutated AAV Capsid Proteins for Hepatic Targeting
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Solution Overview
Problem
Current AAV vectors face challenges with broad tropism and low transduction efficiency, requiring high doses for effective gene transfer, especially in targeting specific liver tissues and hepatocellular carcinoma cells, and are hindered by the immune response and off-target effects.
Innovation Solution
Development of mutated AAV capsid proteins with specific oligopeptide inserts at defined positions, enhancing targeting specificity and efficiency for hepatic tissue, hepatocytes, and hepatocellular carcinoma cells, while minimizing immune response and off-target transduction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional AAV vectors are used for gene transfer, then broad tropism is achieved, but transduction efficiency for specific hepatic tissue and HCC cells remains low
Solution Approach 1:
The patent applies local quality by inserting specific oligopeptide sequences (such as RGD, YGD, or integrin-binding peptides) at defined positions within the AAV2 capsid protein structure. These localized modifications create specific binding sites that confer enhanced affinity for hepatic tissue and HCC cells, transforming the broad, non-specific tropism of wild-type AAV into targeted, high-efficiency transduction of liver-specific cell types.
2Productivity
If high vector doses are administered to compensate for low transduction efficiency, then adequate gene transfer is achieved, but immune response and off-target effects increase
Solution Approach 1:
The patent changes the biochemical parameters of the AAV capsid by incorporating mutated capsid proteins with specific oligopeptide inserts. This modification alters the capsid's surface properties and receptor-binding characteristics, enabling high-affinity interaction with hepatic tissue at low vector doses. Consequently, effective gene transfer is achieved without requiring high doses that would trigger immune responses or cause off-target transduction.
Data Source
AI summary
The present invention relates in a first aspect to a mutated adeno-associated virus (AAV) capsid protein or fragment thereof having an insert composed of an oligopeptide optionally having further amino acids representing linker sequences flanking both sites of said oligopeptide. These mutated AAV capsid proteins are more efficient in targeting hepatic tissue, hepatocytes, hepatic cells and cell lines or hepatocellular carcinoma (HCC) with partially higher specificity. Further, a mutated AAV particle comprising the mutated AAV capsid protein according to the present invention is provided. In addition, a nucleic acid encoding the mutated AAV capsid protein according to the present invention is identified together with a corresponding nucleic acid vector, in particular, a plasmid. In addition, a host cell containing the nucleic acid vector or the nucleic acid molecule according to the present invention. Further, a use of the AAV particle or the nucleic acid or the nucleic acid vector according to the present invention in the manufacture of an AAV particle, or in the manufacture of a medicament for gene therapy is described. Moreover, the described protein, particle molecules as well as nucleic acid vectors for use in targeting hepatocytes and/or HCC are de-scribed. In particular, said components for use in treating diseases involving hepatocytes or for treating HCC are disclosed, in particular, for use in gene therapy, e.g. for use in a transfer of a gene of interest into hepatocytes, heptatic tissue or HCC.