Journal
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
Volume 17, Issue -, Pages 922-935Publisher
CELL PRESS
DOI: 10.1016/j.omtm.2020.04.010
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Funding
- NIH [P01AI100263, R01NS076991, P01HD080642, R01AI12135]
- NIAMS/NIH [R01AR068983, R21AR072836, R21AR073331]
- Glory Harvest Group
- AAVAA Therapeutics
- Center for Skeletal Research Imaging and Biomechanical Testing Core [NIH P30AR066261]
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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 kappa B) 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.
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