Chimeric Envelope Proteins for Lymphocyte-Targeted RNA Virus Vectors
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Solution Overview
Problem
Existing Sendai virus vectors exhibit low gene transfer efficiency into lymphocytes such as B cells, CD4 positive T cells, and CD8 positive T cells, limiting their application in industrial and clinical settings.
Innovation Solution
Pseudo-typing the Sendai virus vector with envelope proteins from Measles virus, specifically combining modified F and H proteins, to enhance fusion efficiency and host cell specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If Sendai virus vector is used for gene transfer, then wide host and cell specificities are achieved, but gene transfer efficiency into lymphocytes (B cells, CD4 positive T cells, CD8 positive T cells) is low
Solution Approach 1:
The patent introduces chimeric envelope proteins as intermediary components that mediate between the Sendai virus vector and lymphocyte cells. These chimeric proteins are formed by combining Sendai virus F protein with Measles virus H protein, creating a hybrid structure that serves as an effective mediator for binding to lymphocyte surface receptors and facilitating membrane fusion, thereby significantly improving gene transfer efficiency into lymphocytes while preserving the wide host range capability.
Solution Approach 2:
The patent applies composite material principles by constructing chimeric envelope proteins that integrate different functional domains from Sendai virus and Measles virus. The F protein from Sendai virus provides fusion activity, while the H protein from Measles virus provides enhanced binding affinity to lymphocyte cells. This composite structure combines the advantages of both parent viruses to achieve both wide host specificity and high lymphocyte-targeted gene transfer efficiency.
2Reliability
If Sendai virus vector is used for gene transfer, then safety is maintained (no pathogenicity, genotoxicity, or tumorigenicity), but gene transfer efficiency into lymphocytes is insufficient
Solution Approach 1:
The patent applies local quality modification by selectively altering only the envelope protein components responsible for cell binding and fusion, while maintaining the safe Sendai virus genome. The chimeric envelope proteins are designed with specific local regions from Measles virus that enhance lymphocyte targeting, without changing the overall safety characteristics of the Sendai virus vector. This localized modification allows improvement of gene transfer efficiency while preserving the inherent safety profile.
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
Facilitates efficient gene transfer into B cells, CD4 positive T cells, and CD8 positive T cells, enhancing applications in gene therapy and regenerative medicine, particularly in establishing induced pluripotent stem cells.
Implementation Method 1
the infection of the Sendai virus and the gene transfer by the recombinant Sendai virus vector occur in two stages of (1) binding of virus particles (vector particles) to cell membranes and (2) fusion of virus outer membranes (envelope) and cell membranes
Implementation Method 2
The HN protein has sialic acid hydrolase (sialidase) activity, and is involved in the binding of virus particles (vector particles) in the first stage to the cell membrane by binding to sialic acid which is a component of glycolipids and glycoproteins present on the cell membrane
Data Source
AI summary
The present invention addresses the problem of providing a chimeric envelope protein that pseudotypes a virus, and also providing efficient gene transfer and gene expression techniques to lymphocytes such as B cells, CD4 positive T cells, and CD8 positive T cells contained in peripheral blood and immortalized cells derived from these cells, said techniques being characterized by using an RNA virus vector having the aforesaid chimeric protein. In a gene transfer method using a single-stranded RNA virus vector such as a Sendai virus vector or a stealth RNA vector, the virus is pseudotyped by using, as the envelope proteins of viral particles, a chimeric F protein having a morbillivirus-derived F protein region and a chimeric H protein having a morbillivirus-derived H protein region.