Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis

Nat Commun. 2019 Jul 4;10(1):2958. doi: 10.1038/s41467-019-10809-6.


RNAi-based bone anabolic gene therapy has demonstrated initial success, but many practical challenges are still unmet. Here, we demonstrate that a recombinant adeno-associated virus 9 (rAAV9) is highly effective for transducing osteoblast lineage cells in the bone. The adaptor protein Schnurri-3 (SHN3) is a promising therapeutic target for osteoporosis, as deletion of shn3 prevents bone loss in osteoporotic mice and short-term inhibition of shn3 in adult mice increases bone mass. Accordingly, systemic and direct joint administration of an rAAV9 vector carrying an artificial-microRNA that targets shn3 (rAAV9-amiR-shn3) in mice markedly enhanced bone formation via augmented osteoblast activity. Additionally, systemic delivery of rAAV9-amiR-shn3 in osteoporotic mice counteracted bone loss and enhanced bone mechanical properties. Finally, we rationally designed a capsid that exhibits improved specificity to bone by grafting the bone-targeting peptide motif (AspSerSer)6 onto the AAV9-VP2 capsid protein. Collectively, our results identify a bone-targeting rAAV-mediated gene therapy for osteoporosis.

Publication types

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

MeSH terms

  • Animals
  • Bone Resorption / complications*
  • Bone Resorption / pathology
  • Bone Resorption / prevention & control*
  • Bone and Bones / metabolism*
  • Bone and Bones / virology
  • Capsid / metabolism
  • Cartilage / virology
  • DNA-Binding Proteins / metabolism*
  • Dependovirus / metabolism*
  • Disease Models, Animal
  • Gene Deletion
  • Gene Silencing*
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Osteoblasts / metabolism
  • Osteoporosis / complications*
  • Serogroup


  • DNA-Binding Proteins
  • Hivep2 protein, mouse