Year: 2019
Type: article
Abstract: 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.
Source: Nature Communications
Institution: University of Massachusetts Chan Medical School
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Health and Human Services, Brigham and Women's Hospital, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Office of Extramural Research, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1233219112, G181471636, G2097806758, Novel approach to promote bone formation in osteoporosis using bone-homing mesenchymal stem cells, G2803930335, G3414764031, G3825480591, G4166271608, Identification of novel regulators governing osteoclast-osteoblast coupling, G4524232403, G4778054082, MITOCHONDRIAL ENCEPHALOMYOPATHIES: APPROACHES TO TREATMENT, G5641026441, G613221410, G6143746593, G6244983776, Novel Gene Therapy Strategies for Canavan Disease, G683224971, G722399606, Novel approaches to the treatment of bone loss in rheumatoid arthritis, G7855069482, A Gene therapeutic approach to stable suppression of HIV-1 replication, G8328322646, G8535024085, G9000029835, G9000084952, G9000097104, G9000106716
OpenAlex ID: W2954037482