AAV Capsid HDL-Binding Moieties for Liver Transduction
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Solution Overview
Problem
Current adeno-associated virus (AAV) vectors face limitations in tissue-specific transduction efficiency, particularly for hepatocytes located further from the portal vein, leading to inadequate intrahepatic distribution and transgene expression, despite advancements in tropism modification and neutralization strategies.
Innovation Solution
Modification of AAV vectors with high-density lipoprotein (HDL)-binding moieties on the capsid proteins, specifically targeting HDL-associated organs like the liver, brain, kidneys, pancreas, spleen, ovaries, and adrenals, by inserting HDL-binding epitopes into exposed loops or fusing them onto the capsid proteins, enhancing vector association with HDL particles for improved transduction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If AAV vectors are administered intravenously to achieve liver transduction, then hepatocyte transduction is improved, but transduction efficiency decreases for hepatocytes located further from the portal vein
Solution Approach 1:
The patent introduces HDL (high-density lipoprotein) as an intermediary carrier that binds to AAV vectors via HDL-binding moieties on the capsid. This intermediary mechanism enables AAV vectors to be transported throughout the bloodstream and distributed to hepatocytes throughout the liver, bypassing the limitation of portal vein proximity and achieving uniform intrahepatic distribution.
Solution Approach 2:
The patent modifies the AAV capsid protein by incorporating HDL-binding moieties (such as ApoA1-binding peptides or antibodies), which changes the binding parameters of the vector. This parameter change enables the vector to bind to HDL particles, fundamentally altering its transport mechanism and distribution pattern within the liver.
2Adaptability or versatility
If conventional AAV vectors are used for gene delivery, then broad tropism allows infection of multiple cell types, but transduction efficiency is insufficient due to inefficient uptake and translocation
Solution Approach 1:
The patent applies local quality modification by specifically enhancing the HDL-binding capability at particular regions of the capsid protein (through insertion of HDL-binding moieties in exposed loops or fusion at N/C termini) while preserving the overall capsid structure and broad tropism characteristics. This localized modification improves transduction efficiency without sacrificing versatility.
Solution Approach 2:
The patent creates a composite structure by combining the AAV capsid protein with HDL-binding moieties (such as peptides, antibodies, or antibody fragments). This composite capsid structure integrates the broad tropism of AAV with the specific HDL-binding capability, resulting in a vector that maintains versatility while achieving enhanced transduction efficiency through HDL-mediated transport.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified AAV vectors demonstrate increased transduction efficiency and spread in target tissues, particularly for hepatocytes distantly located from the portal vein, by leveraging HDL as a natural carrier, thereby enhancing gene therapy delivery at lower vector doses.
Implementation Method 1
The HDL-binding moiety displayed by the modified capsid protein confers to the AAV vectors of the invention the ability to associate with HDL particles in the bloodstream
Data Source
AI summary
The present invention relates to AAV vectors comprising a capsid protein that has been modified to bind to high-density lipoprotein (HDL) by insertion of an HDL-binding moiety into the capsid protein. The HDL-binding moiety can be an HDL-binding protein or domain thereof, such as a single domain antibody like a VHH domain, or the HDL-binding moiety can be an HDL-binding epitope, e.g. derived from an HDL- or ApoA1-binding protein. The HDL-binding moiety is preferably inserted into an exposed loop of the capsid protein. The HDL-binding moiety can be expressed on one, two or all three of the VP1, VP2 and VP3 capsid proteins. The AAV vectors of the invention that to bind to HDL show improved transduction efficiency of liver cells as well as improved spread transduction throughout the liver. The invention therefore further provides for the use of the AAV vectors of the invention in the treatment of conditions that can be treated by gene therapy of the liver.