Department of Medicine, Division of Rheumatology; Horae Gene Therapy Center; Department of Microbiology and Physiological Systems; Viral Vector Core; Li Weibo Institute for Rare Diseases Research
Genetics and Genomics | Musculoskeletal Diseases | Musculoskeletal System | Nucleic Acids, Nucleotides, and Nucleosides | Nutritional and Metabolic Diseases | Therapeutics
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.
Gene therapy, Metabolic bone disease, siRNAs
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Copyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Nat Commun. 2019 Jul 4;10(1):2958. doi: 10.1038/s41467-019-10809-6. Link to article on publisher's site
Yang, Yeon-Suk; Xie, Jun; Wang, Dan; Kim, Jung-Min; Tai, Phillip W. L.; Gravallese, Ellen M.; Gao, Guangping; and Shim, Jae-Hyuck, "Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis" (2019). Open Access Articles. 3930.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
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