Humanized AAV Vectors Masking Immune Clearance
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Solution Overview
Problem
Pre-existing immunity and adaptive immune responses to adeno-associated virus (AAV) vectors hinder consistent and efficient gene transfer and long-term expression of therapeutic genes in humans, limiting the effectiveness of viral vector-based gene therapy due to antibody-mediated clearance and immune responses.
Innovation Solution
Development of humanized viral vectors, specifically adeno-associated virus vectors, where human proteins such as human serum albumin are affixed to the capsid surface, masking antigenic epitopes and evading immune recognition, allowing for efficient delivery even in the presence of pre-existing antibodies and enabling multiple administrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional AAV vectors are used for gene delivery, then gene transfer can be achieved in vitro and in vivo, but pre-existing immunity and adaptive immune responses cause antibody-mediated clearance, reducing delivery efficiency and preventing re-administration
Solution Approach 1:
Human serum albumin (HSA) is used as an intermediary coating on the AAV capsid surface. This HSA layer acts as a mediator that masks the viral epitopes, preventing direct recognition by the immune system while still allowing the vector to perform its gene delivery function. The HSA coating enables the vector to evade antibody-mediated clearance and immune surveillance.
Solution Approach 2:
The surface properties of the AAV vector are modified by coating with human proteins, changing the immunogenic parameters of the vector. This parameter change transforms the vector from being highly immunogenic to being immunologically camouflaged, allowing it to circulate in the bloodstream without triggering immune responses and enabling repeated administrations.
2Productivity
If AAV vectors are administered to achieve therapeutic gene expression, then consistent and efficient gene transfer can be obtained, but pre-existing antibodies clear the vectors, limiting long-term expression and re-administration capability
Solution Approach 1:
Human serum albumin serves as a protective intermediary that shields the AAV vector from immune clearance. This coating allows the vector to maintain its gene delivery productivity while extending its duration of action by preventing antibody-mediated elimination, thereby enabling long-term therapeutic gene expression and multiple dosing regimens.
Solution Approach 2:
The invention converts the harmful effect of pre-existing immunity into a benefit by using human proteins that the immune system recognizes as self. The HSA coating, which could be seen as an additional layer complicating the system, actually provides the benefit of immune evasion, allowing the vector to persist longer in the body and maintain therapeutic expression.
Data Source
AI summary
The present invention provides humanized viral vectors and methods of use thereof for delivery of transgenes or therapeutic nucleic acids to human subjects. Humanized viral vectors are modified from known viral vectors such as those based on AAV by coating their surface with a human protein such as human serum albumin and optionally a lipid coating or formulation, so that the foreign or non-human nature of the vector is masked. The coating is performed in a manner that reduces or prevents binding of antibodies to the vector surface, thereby reducing or preventing antibody-mediated clearance of vector, but still allowing the vector to transduce target cells and achieve therapeutic gene transfer. Such humanized vectors therefore evade pre-existing immune surveillance, reduce immune responses, and achieve therapeutic gene transfer in the presence of pre-existing antibodies to the viral vector.