Engager-mediated targeting of lentiviral vectors to specific cell types

VSV-G-pseudotyped lentiviral vectors (LVV) are leading tools for CAR-T and gene therapy. These treatments are highly effective, but are complex and very expensive. Recently, major efforts aim at developing in vivo procedures for CAR-T and gene therapy, aiming at developing cell-specific vectors, thereby eliminating the need to harvest cells from each patient individually. Pseudotyping with VSV-G provides stable vectors, but their broad tropism limits in vivo applications. Our prior research revealed that VSV infects cells through binding to the ubiquitously expressed low-density lipoprotein receptor (LDLR) and its family members, which accounts for its extensive tropism. Upon administration, most vector particles will be lost by transducing cells non-specifically. To provide specificity, we have engineered engager molecules consisting of the VSV-G-binding domain of LDLR fused to ligands of cell-specific receptors. In preliminary studies, we demonstrated that LVV pre-coated with an engager selectively transduced traget cells while preventing non-specific transduction. Specifically, we observed selective transduction of human epithelial cells whereas primary human fibroblasts are not transduced. These findings hold significant potential for advancing the clinical application of in vivo CAR-T and gene therapy.