Pseudotyped Viral Vectors with Heterologous Targeting Moieties
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Solution Overview
Problem
Current pseudotyped viruses have limitations in terms of transduction efficiency and specificity, particularly when used for gene therapy and cancer treatment.
Innovation Solution
The development of pseudotyped viral-like particles or viral vectors that incorporate a targeting polypeptide with a heterologous targeting moiety linked to an envelope glycoprotein G or H of a Paramyxoviridae family virus, along with a truncated protein lacking a targeting moiety and a glycoprotein F, to enhance transduction efficiency and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If pseudotyped viral vectors are used to alter host range, then the receptor phenotype is changed to achieve broader or narrowed host range, but transduction efficiency and specificity are limited
Solution Approach 1:
The envelope glycoprotein is segmented into multiple functional domains: a Paramyxoviridae family envelope glycoprotein G or H domain for receptor binding, a heterologous targeting moiety domain for specific cell targeting, and a linkage domain connecting them. This segmentation allows each domain to be optimized independently for its specific function while working together to achieve both broad host range and high transduction efficiency.
Solution Approach 2:
The viral vector envelope is constructed as a composite structure combining different glycoprotein components: the Paramyxoviridae family envelope glycoprotein G or H provides the basic viral envelope structure and receptor interaction, while the heterologous targeting moiety (such as antibodies, antibody fragments, or other binding proteins) provides specific targeting capabilities. This composite approach integrates the advantages of both components to achieve enhanced transduction efficiency and specificity.
2Measurement precision
If a targeting moiety is linked to the envelope glycoprotein, then specific cell targeting is achieved, but the structural complexity of the viral particle increases
Solution Approach 1:
The targeting function is extracted as a separate heterologous targeting moiety that can be independently designed and optimized, then linked to the envelope glycoprotein. This extraction allows the targeting moiety to be selected from various options (antibodies, antibody fragments, other binding proteins) without redesigning the entire viral particle structure, thereby achieving high targeting specificity while managing structural complexity.
Solution Approach 2:
A linkage domain or peptide linker acts as an intermediary between the envelope glycoprotein and the heterologous targeting moiety. This intermediary element provides a stable connection while allowing the targeting moiety to maintain its binding specificity for the target cell surface. The linkage domain facilitates the integration of different functional components without creating excessive structural complexity.
Data Source
AI summary
Provided for herein are compositions and methods that can be used to transduce cells and deliver genetic information that can then be expressed in the transduced cell. Also provided herein are methods of treating a disease in a subject using the compositions and methods provided.