Gene and Cell therapy using selective transducing vectors

Currently approved clinical protocols enable gene therapy using hematopoietic stem cells, and treatment of hematopoietic malignancies by generating T cells expressing chimeric antigen receptors (CAR-T). These protocols are rather complicated, time consuming and very expensive, limiting their broad clinical implementation. They require isolation of the cells from each patient individually, and following gene transfer, the cells need to be amplified ex vivo. The cells then need to go extensive purification and quality control before administering them back to the patient. One possible approach to reduce the time, cost and complexity of these procedure is to develop vectors that can be administered in vivo. If developed, such vectors will serve as universal “off the shelf” therapies, rather than having to generate tailor-made cells for each patient individually.

Gene therapy and CAR-T are currently based on cell transduction using viral vectors. VSV-G-pseudotyped lentiviral vectors (LVV) are the vectors of choice, as they are rather stable and exhibit relatively high transduction efficiency. However, these vectors are not suitable for in vivo gene therapy as they are non-specific, transducing a broad range of cell types through the ubiquitously-expressed LDL receptor (LDLR) and its other family members. To allow cell specificity while still benefiting from the advantages of VSV-G-pseudotyped LVVs, we developed adapter proteins, consisting of the ligand-binding domain of LDLR, fused to a ligand of a receptor present on a specific cell type. These Adapters allowed transduction through a cell-specific receptor while preventing non-specific vector entry through the ubiquitous LDLR.