AAV-mediated delivery of osteoblast/osteoclast-regulating miRNAs for osteoporosis therapy

Aijaz Ahmad John; Jun Xie; Yeon-Suk Yang; Jung-Min Kim; Chujiao Lin; Hong Ma; Guangping Gao; Jae-Hyuck Shim

Molecular Therapy: Nucleic Acids (Sep 2022)

AAV-mediated delivery of osteoblast/osteoclast-regulating miRNAs for osteoporosis therapy

Aijaz Ahmad John,
Jun Xie,
Yeon-Suk Yang,
Jung-Min Kim,
Chujiao Lin,
Hong Ma,
Guangping Gao,
Jae-Hyuck Shim

Affiliations

Aijaz Ahmad John: Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, USA
Jun Xie: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, USA; Viral Vector Core, University of Massachusetts Chan Medical School, Worcester, MA, USA
Yeon-Suk Yang: Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, USA
Jung-Min Kim: Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, USA
Chujiao Lin: Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, USA
Hong Ma: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, USA; Viral Vector Core, University of Massachusetts Chan Medical School, Worcester, MA, USA
Guangping Gao: Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, USA; Viral Vector Core, University of Massachusetts Chan Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA; Corresponding author. Guangping Gao, Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Jae-Hyuck Shim: Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, USA; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA; Corresponding author. Jae-Hyuck Shim, Department of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, USA.

Journal volume & issue: Vol. 29
pp. 296 – 311

Abstract

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Osteoporosis occurs due to a dysregulation in bone remodeling, a process requiring both bone-forming osteoblasts and bone-resorbing osteoclasts. Current leading osteoporosis therapies suppress osteoclast-mediated bone resorption but show limited therapeutic effects because osteoblast-mediated bone formation decreases concurrently. We developed a gene therapy strategy for osteoporosis that simultaneously promotes bone formation and suppresses bone resorption by targeting two microRNAs (miRNAs)—miR-214-3p and miR-34a-5p. We modulated the expression of these miRNAs using systemically delivered recombinant adeno-associated viral (rAAV) vectors targeting the bone. rAAV-mediated overexpression of miR-214-3p or inhibition of miR-34a-5p in the skeleton resulted in bone loss in adult mice, resembling osteoporotic bones. Conversely, rAAV-mediated inhibition of miR-214-3p or overexpression of miR-34a-5p reversed bone loss in mouse models for postmenopausal and senile osteoporosis by increasing osteoblast-mediated bone formation and decreasing osteoclast-mediated bone resorption. Notably, these mice did not show any apparent pathological phenotypes in non-skeletal tissues. Mechanistically, inhibiting miR-214-3p upregulated activating transcription factor 4 in osteoblasts and phatase and tensin homolog in osteoclasts, while overexpressing miR-34a-5p downregulated Notch1 in osteoblasts and TGF-β-induced factor homeobox 2 in osteoclasts. In summary, bone-targeting rAAV-mediated regulation of miR-214-3p or miR-34a-5p is a promising new approach to treat osteoporosis, while limiting adverse effects in non-skeletal tissues.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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