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Bone-Targeting AAV-Mediated Gene Silencing in Osteoclasts for Osteoporosis Therapy

Authors
 Yeon-Suk Yang  ;  Jun Xie  ;  Sachin Chaugule  ;  Dan Wang  ;  Jung-Min Kim  ;  JiHea Kim  ;  Phillip W L Tai  ;  Seok-Kyo Seo  ;  Ellen Gravallese  ;  Guangping Gao  ;  Jae-Hyuck Shim 
Citation
 MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT, Vol.17 : 922-935, 2020-06 
Journal Title
 MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 
Issue Date
2020-06
Keywords
artificial miRNA ; bone formation ; bone resorption ; cathepsin k ; osteoblast ; osteoclast ; osteoclastogenesis ; osteoporosis ; rAAV ; rank
Abstract
Improper activity of bone-resorbing osteoclasts results in low bone density and deterioration of bone structure, which increase the risk of fractures. Anti-resorptive therapies targeting osteoclasts have proven effective in preserving bone mass, but these therapeutic agents lead to defective new bone formation and numerous potential side effects. In this study, we demonstrate that recombinant adeno-associated virus, serotype 9 (rAAV9) can deliver to osteoclasts an artificial microRNA (amiR) that silences expression of key osteoclast regulators, RANK (receptor activator for nuclear factor κB) and cathepsin K (rAAV9.amiR-rank, rAAV9.amiR-ctsk), to prevent bone loss in osteoporosis. As rAAV9 is highly effective for the transduction of osteoclasts, systemic administration of rAAV9 carrying amiR-rank or amiR-ctsk results in a significant increase of bone mass in mice. Furthermore, the bone-targeting peptide motif (Asp)14 or (AspSerSer)6 was grafted onto the AAV9-VP2 capsid protein, resulting in significant reduction of transgene expression in non-bone peripheral organs. Finally, systemic delivery of bone-targeting rAAV9.amiR-ctsk counteracts bone loss and improves bone mechanical properties in mouse models of postmenopausal and senile osteoporosis. Collectively, inhibition of osteoclast-mediated bone resorption via bone-targeting rAAV9-mediated silencing of ctsk is a promising gene therapy that can preserve bone formation and mitigate osteoporosis, while limiting adverse off-target effects.
Files in This Item:
T202002391.pdf Download
DOI
10.1016/j.omtm.2020.04.010
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers
Yonsei Authors
Seo, Seok Kyo(서석교) ORCID logo https://orcid.org/0000-0003-3404-0484
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/179296
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