WNT-modulating gene silencers as a gene therapy for osteoporosis, bone fracture, and critical-sized bone defects

Won-Taek Oh; Yeon-Suk Yang; Jun Xie; Hong Ma; Jung-Min Kim; Kwang-Hwan Park; Daniel S Oh; Kyung-Hyun Park-Min; Matthew B Greenblatt; Guangping Gao; Jae-Hyuck Shim

doi:10.1016/j.ymthe.2022.09.018

WNT-modulating gene silencers as a gene therapy for osteoporosis, bone fracture, and critical-sized bone defects

Mol Ther. 2023 Feb 1;31(2):435-453. doi: 10.1016/j.ymthe.2022.09.018. Epub 2022 Oct 3.

Authors

Affiliations

¹ Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, 364 Plantation Street. LRB 217, Worcester, MA 01605, USA; Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul 03722, Korea.
² Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, 364 Plantation Street. LRB 217, Worcester, MA 01605, USA.
³ Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 368 Plantation Street AS6-2049, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, 368 Plantation Street AS6-2049, Worcester, MA 01605, USA; Viral Vector Core, University of Massachusetts Chan Medical School, 368 Plantation Street AS6-2049, Worcester, MA 01605, USA.
⁴ Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul 03722, Korea.
⁵ Osteogene Tech, Norwood, NJ 07648, USA.
⁶ Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA; Research Division, Hospital for Special Surgery, New York, NY 10021, USA.
⁷ Research Division, Hospital for Special Surgery, New York, NY 10021, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
⁸ Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 368 Plantation Street AS6-2049, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, 368 Plantation Street AS6-2049, Worcester, MA 01605, USA; Viral Vector Core, University of Massachusetts Chan Medical School, 368 Plantation Street AS6-2049, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, 368 Plantation Street AS6-2049, Worcester, MA 01605, USA. Electronic address: guangping.gao@umassmed.edu.
⁹ Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, 364 Plantation Street. LRB 217, Worcester, MA 01605, USA; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 368 Plantation Street AS6-2049, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, 368 Plantation Street AS6-2049, Worcester, MA 01605, USA. Electronic address: jaehyuck.shim@umassmed.edu.

Abstract

Treating osteoporosis and associated bone fractures remains challenging for drug development in part due to potential off-target side effects and the requirement for long-term treatment. Here, we identify recombinant adeno-associated virus (rAAV)-mediated gene therapy as a complementary approach to existing osteoporosis therapies, offering long-lasting targeting of multiple targets and/or previously undruggable intracellular non-enzymatic targets. Treatment with a bone-targeted rAAV carrying artificial microRNAs (miRNAs) silenced the expression of WNT antagonists, schnurri-3 (SHN3), and sclerostin (SOST), and enhanced WNT/β-catenin signaling, osteoblast function, and bone formation. A single systemic administration of rAAVs effectively reversed bone loss in both postmenopausal and senile osteoporosis. Moreover, the healing of bone fracture and critical-sized bone defects was also markedly improved by systemic injection or transplantation of AAV-bound allograft bone to the osteotomy sites. Collectively, our data demonstrate the clinical potential of bone-specific gene silencers to treat skeletal disorders of low bone mass and impaired fracture repair.

Keywords: bone fracture; critical-sized bone defect; osteoblast; osteoclast; osteoporosis; rAAV; schnurri-3; sclerostin; skeletal organoid.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Bone and Bones
Fractures, Bone* / genetics
Fractures, Bone* / therapy
Genetic Therapy
Humans
Osteoporosis* / genetics
Osteoporosis* / therapy

Substances

Adaptor Proteins, Signal Transducing

Abstract

Publication types

MeSH terms

Substances

Grants and funding