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.

Details

Title
Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis
Author
Yeon-Suk Yang 1 ; Xie, Jun 2   VIAFID ORCID Logo  ; Wang, Dan 3   VIAFID ORCID Logo  ; Jung-Min, Kim 1 ; Tai, Phillip W L 3   VIAFID ORCID Logo  ; Gravallese, Ellen 1 ; Gao, Guangping 4   VIAFID ORCID Logo  ; Jae-Hyuck Shim 5 

1  Department of Medicine/Division of Rheumatology, University of Massachusetts Medical School, Worcester, MA, USA 
2  Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA; Viral Vector Core, University of Massachusetts Medical School, Worcester, MA, USA 
3  Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA 
4  Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA; Viral Vector Core, University of Massachusetts Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA 
5  Department of Medicine/Division of Rheumatology, University of Massachusetts Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA 
Pages
1-13
Publication year
2019
Publication date
Jul 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-10809-6
ProQuest document ID
2252270923
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.