한빛사 논문
Yeon-Suk Yang1,6, Jun Xie2,3,4,6, Dan Wang2,3, Jung-Min Kim1, Phillip W.L. Tai2,3, Ellen Gravallese1, Guangping Gao2,3,4,5,* & Jae-Hyuck Shim1,5,*
1 Department of Medicine/Division of Rheumatology, University of Massachusetts Medical School, Worcester, MA 01605, USA. 2 Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA. 3 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA. 4 Viral Vector Core, University of Massachusetts Medical School, Worcester, MA 01605, USA. 5 Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA. 6 These authors contributed equally: Yeon-Suk Yang, Jun Xie
*Correspondence and requests for materials should be addressed to G.G. or to J.-H.S.
Abstract
RNAi-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 of shn3 prevents bone loss in osteoporotic mice and short-term inhibition of shn3 in adult mice increases bone mass. Accordingly, systemic and direct joint administration of an rAAV9 vector carrying an artificial-microRNA that targets shn3 (rAAV9-amiR-shn3) in mice markedly enhanced bone formation via augmented osteoblast activity. Additionally, systemic delivery of rAAV9-amiR-shn3 in 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)6 onto the AAV9-VP2 capsid protein. Collectively, our results identify a bone-targeting rAAV-mediated gene therapy for osteoporosis.
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