심재혁 (University of Massachusetts Chan Medical School) | 한빛사논문 > 한빛사

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University of Massachusetts Chan Medical School

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Mol. Ther., Jun 26 2024, S1525-0016(24)00426-X | https://doi.org/10.1016/j.ymthe.2024.06.036 Engineering a targeted and safe bone anabolic gene therapy to treat osteoporosis in alveolar bone loss

Chujiao Lin ¹, Yeon-Suk Yang¹, Hong Ma ^2,3,4,5, Zhihao Chen ¹, Dong Chen ^6,7, Aijaz Ahmad John ¹, Jun Xie^2,3,4,5, Guangping Gao ^2,3,4,5,8*, Jae-Hyuck Shim ^1,3,8*

¹Department of Medicine/Division of Rheumatology, UMass Chan Medical School, Worcester, MA, 01655, USA

²Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, 01655, USA

³Horae Gene Therapy Center,

⁴Department of Microbiology and Physiological Systems,

⁵Viral Vector Core, UMass Chan Medical School, Worcester, MA, 01655, USA

⁶State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China

⁷Department of Implantology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China

⁸Li Weibo Institute for Rare Diseases Research, UMass Chan Medical School, Worcester, MA, 01655, USA

^*To whom correspondence should be addressed. : Guangping Gao, Jae-Hyuck Shim

Abstract

Alveolar bone loss in elderly populations is highly prevalent and increases the risk of tooth loss, gum disease susceptibility, and facial deformity. Unfortunately, there are very limited treatment options available. Here, we developed a bone-targeted gene therapy that reverses alveolar bone loss in patients with osteoporosis by targeting the adaptor protein Schnurri-3 (SHN3). SHN3 is a promising therapeutic target for alveolar bone regeneration, because SHN3 expression is elevated in human and mouse mandible tissues with osteoporosis while deletion of SHN3 in mice greatly increases alveolar bone and tooth dentin mass. We used a bone-targeted recombinant adeno-associated virus (rAAV) carrying an artificial microRNA (miRNA) that silences SHN3 expression to restore alveolar bone loss in mouse models of both postmenopausal and senile osteoporosis by enhancing WNT signaling and osteoblast function. Additionally, rAAV-mediated silencing of SHN3 enhanced bone formation and collagen production of human skeletal organoids in xenograft mice. Finally, rAAV expression in the mandible was tightly controlled via liver- and heart-specific miRNA-mediated repression or via a vibration-inducible mechanism. Collectively, our results demonstrate that AAV-based bone anabolic gene therapy is a promising strategy to treat alveolar bone loss in osteoporosis.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-07-02)
연구진국외 연구진
분야 의약학 > 응용의학

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