{"doi":"10.1016/j.omtn.2023.102111","title":"AAV-based gene editing of type 1 collagen mutation to treat osteogenesis imperfecta","abstract":"Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility, low bone mass, fractures, and extraskeletal manifestations. Since OI is commonly caused by single-nucleotide mutation(s) in the COL1A1 or COL1A2 genes encoding type I collagens, we developed a genome-editing strategy to correct a Col1a2 mutation in an OIM mouse model resembling a severe dominant form of human type III OI. Using a recombinant adeno-associated virus (rAAV), we delivered CRISPR-Cas9 to bone-forming osteoblast-lineage cells in the skeleton. Homology-directed repair (HDR)–mediated gene editing efficiency in these cells was improved when CRISPR-Cas9 was coupled with a donor AAV vector containing a promoterless partial mouse Col1a2 complementary DNA sequence. This approach effectively reversed the dysregulation of osteogenic differentiation by a Col1a2 mutation in vitro . Furthermore, systemic administration of dual rAAVs in OIM mice lowered bone matrix turnover rates by reducing osteoblast and osteoclast development while improving the cellular network of mechano-sensing osteocytes embedded in the bone matrix. This strategy significantly improved bone architecture/mass/mineralization, skeletal deformities, grip strength, and spontaneous fractures. Our study is the first demonstration that HDR-mediated gene editing via AAV-mediated delivery effectively corrects a collagen mutation in OI osteoblasts and reverses skeletal phenotypes in OIM mice.","journal":"Molecular Therapy — Nucleic Acids","year":2023,"id":335792,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":290640,"name":"Tadatoshi Sato","orcid":null,"position":1,"is_corresponding":false},{"id":353853,"name":"Sachin Chaugule","orcid":"0000-0001-6323-2034","position":2,"is_corresponding":false},{"id":1065769,"name":"Hong Mā","orcid":"0000-0001-8717-4422","position":3,"is_corresponding":false},{"id":451309,"name":"Jun Xie","orcid":"0000-0002-9385-3242","position":4,"is_corresponding":false},{"id":226490,"name":"Guangping Gao","orcid":"0000-0003-0097-9012","position":5,"is_corresponding":false},{"id":106895,"name":"Jae‐Hyuck Shim","orcid":"0000-0002-4947-3293","position":6,"is_corresponding":false},{"id":283829,"name":"Yeon-Suk Yang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T01:10:02.777338Z","pmid":"38261950","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}