Authors: Yeon-Suk Yang, Jun Xie, Dan Wang, Jung-Min Kim, Phillip W. L. Tai, Ellen Gravallese, Guangping Gao, Jae-Hyuck Shim
Published: 2019-07-04
DOI: 10.1038/s41467-019-10809-6
Source: Full article
AbstractRNAi-based bone anabolic gene therapy has demonstrated initial success, but many practical challenges are still unmet. Here, we demonstrate that a recombinant adeno-associated virus 9 (rAAV9) is highly effective for transducing osteoblast lineage cells in the bone. The adaptor protein Schnurri-3 (SHN3)is a promising therapeutic target for osteoporosis, as deletion ofshn3prevents bone loss in osteoporotic mice and short-term inhibition ofshn3in adult mice increases bone mass. Accordingly, systemic and direct joint administration of an rAAV9 vector carrying an artificial-microRNA that targetsshn3(rAAV9-amiR-shn3) in mice markedly enhanced bone formation via augmented osteoblast activity. Additionally, systemic delivery of rAAV9-amiR-shn3in osteoporotic mice counteracted bone loss and enhanced bone mechanical properties. Finally, we rationally designed a capsid that exhibits improved specificity to bone by grafting the bone-targeting peptide motif (AspSerSer)6onto the AAV9-VP2 capsid protein. Collectively, our results identify a bone-targeting rAAV-mediated gene therapy for osteoporosis.