{"doi":"10.1016/j.omtm.2023.05.020","title":"Development of an AAV-CRISPR-Cas9-based treatment for dominant cone-rod dystrophy 6","abstract":"Cone-rod dystrophy 6 (CORD6) is caused by gain-of-function mutations in the GUCY2D gene, which encodes retinal guanylate cyclase-1 (RetGC1). There are currently no treatments available for this autosomal dominant disease, which is characterized by severe, early-onset visual impairment. The purpose of our study was to develop an adeno-associated virus (AAV)-CRISPR-Cas9-based approach referred to as \"ablate and replace\" and evaluate its therapeutic potential in mouse models of CORD6. This two-vector system delivers (1) CRISPR-Cas9 targeted to the early coding sequence of the wild-type and mutant GUCY2D alleles and (2) a CRISPR-Cas9-resistant cDNA copy of GUCY2D (\"hardened\" GUCY2D ). Together, these vectors knock out (\"ablate\") expression of endogenous RetGC1 in photoreceptors and supplement (\"replace\") a healthy copy of exogenous GUCY2D. First, we confirmed that ablation of mutant R838S GUCY2D was therapeutic in a transgenic mouse model of CORD6. Next, we established a proof of concept for \"ablate and replace\" and optimized vector doses in Gucy2e +/− : Gucy2f −/− and Gucy2f −/− mice, respectively. Finally, we confirmed that the \"ablate and replace\" approach stably preserved retinal structure and function in a novel knockin mouse model of CORD6, the RetGC1 (hR838S, hWT) mouse. Taken together, our results support further development of the \"ablate and replace\" approach for treatment of CORD6.","journal":"Molecular Therapy — Methods & Clinical Development","year":2023,"id":362265,"datarank":0.40128407790441645,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0717003913039835,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0717003913039835,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":8,"citers_with_citation_signal":6,"citers_with_endowment":6,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"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":493767,"name":"Kaitlyn R. Calabro","orcid":"0000-0003-2943-0904","position":1,"is_corresponding":false},{"id":959861,"name":"K. Tyler McCullough","orcid":null,"position":2,"is_corresponding":false},{"id":494718,"name":"Sean M. Crosson","orcid":null,"position":3,"is_corresponding":false},{"id":1115859,"name":"Alejandro de la Cova","orcid":null,"position":4,"is_corresponding":false},{"id":494721,"name":"Diego Fajardo","orcid":null,"position":5,"is_corresponding":false},{"id":723369,"name":"Emily Xu","orcid":"0000-0002-6066-8147","position":6,"is_corresponding":false},{"id":316552,"name":"Sanford L. Boye","orcid":"0000-0002-7312-3197","position":7,"is_corresponding":false},{"id":494719,"name":"Russell Mellen","orcid":null,"position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:14:19.266946Z","pmid":"37361352","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":[]}