Targeted delivery of siRNA to human T cells in humanized mice

초록

siRNA delivery to T lymphocytes remains a major hurdle for harnessing RNAi as a therapeutic strategy, especially in HIV infections. A single chain antibody specific to a pan T cell surface antigen CD7 (scFvCD7) conjugated to a positively charged oligo-9-arginine peptide was used for targeted delivery of siRNA to T cells. The approach was tested in NOD/SCIDIL2r c-/- mice reconstituted with human peripheral blood lymphocytes (Hu-PBL) or hematopoietic stem cells (Hu-HSC). Intravenous administration of scFvCD7-9R/CD4siRNA complexes resulted in efficient CD4 gene silencing in human T cells. In HIV-infected Hu-PBL mice, treatment with a combination of siRNAs targeting cellular CCR5 and viral genes complexed to scFvCD7-9R efficiently controlled viral replication and prevented CD4 T cell loss for up to 5 weeks after infection. Strikingly, this approach also suppressed endogenous virus in mice reconstituted with HIV seropositive PBMC leading to restoration of CD4 T cell counts. Moreover, scFvCD7-9R could also deliver siRNAs to naive T cells in Hu-HSC mice, rendering them resistant to HIV-challenge ex vivo. Our data suggest that scFvCD7-9R is an efficient tool for the delivery of siRNA to T cells in addition to being a promising approach for RNAi-mediated therapy of HIV-1.