Yang Yeon-Suk, Xie Jun, Chaugule Sachin, Wang Dan, Kim Jung-Min, Kim JiHea, Tai Phillip W L, Seo Seok-Kyo, Gravallese Ellen, Gao Guangping, Shim Jae-Hyuck
Division of Rheumatology, University of Massachusetts Medical School, Worcester, MA, USA.
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
Mol Ther Methods Clin Dev. 2020 Apr 18;17:922-935. doi: 10.1016/j.omtm.2020.04.010. eCollection 2020 Jun 12.
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., rAAV9.), to prevent bone loss in osteoporosis. As rAAV9 is highly effective for the transduction of osteoclasts, systemic administration of rAAV9 carrying or results in a significant increase of bone mass in mice. Furthermore, the bone-targeting peptide motif (Asp) or (AspSerSer) 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. 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 is a promising gene therapy that can preserve bone formation and mitigate osteoporosis, while limiting adverse off-target effects.
骨吸收破骨细胞的异常活动会导致骨密度降低和骨结构恶化，从而增加骨折风险。针对破骨细胞的抗吸收疗法已被证明在维持骨量方面有效，但这些治疗药物会导致新骨形成缺陷和许多潜在的副作用。在本研究中，我们证明重组腺相关病毒9型（rAAV9）可以将人工微小RNA（amiR）递送至破骨细胞，该微小RNA可沉默关键破骨细胞调节因子核因子κB受体激活剂（RANK）和组织蛋白酶K的表达（rAAV9.，rAAV9.），以预防骨质疏松症中的骨质流失。由于rAAV9对破骨细胞的转导非常有效，全身给予携带或的rAAV9会导致小鼠骨量显著增加。此外，将骨靶向肽基序（Asp）或（AspSerSer）嫁接到AAV9-VP2衣壳蛋白上，可显著降低非骨外周器官中的转基因表达。最后，在绝经后和老年性骨质疏松症小鼠模型中，全身递送骨靶向rAAV9可抵消骨质流失并改善骨力学性能。总的来说，通过骨靶向rAAV9介导的沉默来抑制破骨细胞介导的骨吸收是一种有前景的基因疗法，它可以维持骨形成并减轻骨质疏松症，同时限制不良的脱靶效应。
