UCLA researchers in the Division of Hematology and Oncology in the Department of Medicine, have discovered novel lentiviral vectors that can be used for gene delivery to B-cells and for the development of neutralizing antibodies against viruses.
BACKGROUND: Microbial tropism is a microbiology term that describes the types of animals (including human), cells, organs, and/or tissues that a particular species and/or strain of pathogen can infect. In virology, how viruses bind host molecules and enter host cells dictate functional tropism. This is clearly seen in the case of HIV-1 virus, where the viral envelope protein GP160 binds to human CD4 molecules, which are present on helper T-cells and macrophages. This allows HIV-1 to specifically infect these cell types. Understanding and modulating cell receptor tropism can be used to understand and inhibit the entry of multiple viral classes into cells. Given that viruses are used to deliver therapeutic molecules to cells in gene therapy settings, understanding viral tropisms is important for the development of efficient gene delivery methods for gene therapy.
INNOVATION: Researchers led by Dr. Koki Morizono have demonstrated that B cell receptors (BCRs) that recognize viral envelope protein epitopes can mediate the binding and cell entry of lentiviral vectors for gene therapy. Additionally, these novel findings aid the understanding of the tropisms of pathogenic viruses such as replication-competent ZIKV and SARS-CoV-2. Gene therapy can now be focused to target specific B cell subpopulations in an antigen-specific manner through pseudotyping vectors with particular viral envelope proteins and/or conjugating desired antigens on the surface of the vectors.
POTENTIAL APPLICATIONS:
- Design of gene therapy and vector-based vaccines
- Aid in the ongoing understanding of immunogenetic adaptation to viral pathogens
ADVANTAGES:
- Identified and developed a specific genetic strategy for isolating BCR and antibody sequences that encode neutralizing antibodies.
- Developed efficient gene delivery methods to B cells in vivo by systemic administration of gene therapy vectors.
- Created new opportunities for antigen-specific gene therapy
- Identified and developed strategies for delivery of therapeutic genes to B cells recognizing and responding to particular types of antigens derived from pathogens, cancers, and/or autoantigens in autoimmune diseases
DEVELOPMENT-TO-DATE: Researchers led by Dr. Koki Morizono have used mice with no prior exposure to any form of pseudotyping envelope proteins.
Related Papers (from the inventors only): Takano, K. A., Wong, A. A. L., Brown, R., Situ, K., Chua, B. A., Abu, A. E., Pham, T. T., Reyes, G. C., Ramachandran, S., Kamata, M., Li, M. M. H., Wu, T. T., Rao, D. S., Arumugaswami, V., Dorshkind, K., Cole, S., & Morizono, K. (2024). Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo. Molecular therapy (In Press)