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

TitleWNT-modulating gene silencers as a gene therapy for osteoporosis, bone fracture, and critical-sized bone defects.
Publication TypeJournal Article
Year of Publication2023
AuthorsOh W-T, Yang Y-S, Xie J, Ma H, Kim J-M, Park K-H, Oh DS, Park-Min K-H, Greenblatt MB, Gao G, Shim J-H
JournalMol Ther
Date Published2023 Feb 01
KeywordsAdaptor Proteins, Signal Transducing, Bone and Bones, Fractures, Bone, Genetic Therapy, Humans, Osteoporosis

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.

Alternate JournalMol Ther
PubMed ID36184851
PubMed Central IDPMC9931550
Grant ListR01 AR078230 / AR / NIAMS NIH HHS / United States
P01 AI100263 / AI / NIAID NIH HHS / United States
P01 HD080642 / HD / NICHD NIH HHS / United States
R21 AR077557 / AR / NIAMS NIH HHS / United States
R01 NS076991 / NS / NINDS NIH HHS / United States
R01 AR075585 / AR / NIAMS NIH HHS / United States
Related Faculty: 
Matthew B. Greenblatt, M.D., Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700