{"doi":"10.1016/j.ajhg.2023.10.005","title":"Efficient in vivo prime editing corrects the most frequent phenylketonuria variant, associated with high unmet medical need","abstract":"The c.1222C>T (p.Arg408Trp) variant in the phenylalanine hydroxylase gene (PAH) is the most frequent cause of phenylketonuria (PKU), the most common inborn error of metabolism. This autosomal-recessive disorder is characterized by accumulation of blood phenylalanine (Phe) to neurotoxic levels. Using real-world data, we observed that despite dietary and medical interventions, most PKU individuals harboring at least one c.1222C>T variant experience chronic, severe Phe elevations and do not comply with Phe monitoring guidelines. Motivated by these findings, we generated an edited c.1222C>T hepatocyte cell line and humanized c.1222C>T mouse models, with which we demonstrated efficient in vitro and in vivo correction of the variant with prime editing. Delivery via adeno-associated viral (AAV) vectors reproducibly achieved complete normalization of blood Phe levels in PKU mice, with up to 52% whole-liver corrective PAH editing. These studies validate a strategy involving prime editing as a potential treatment for a large proportion of individuals with PKU.","journal":"The American Journal of Human Genetics","year":2023,"id":322561,"datarank":0.5606504427425053,"base_score":3.7376696182833684,"endowment":3.7376696182833684,"self_citation_contribution":0.5606504427425053,"citation_network_contribution":0.0,"self_endowment_contribution":0.5606504427425053,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":41,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"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":875167,"name":"Madelynn N. Whittaker","orcid":"0000-0002-3382-1134","position":1,"is_corresponding":false},{"id":1031767,"name":"Ping Qü","orcid":"0009-0005-6442-6558","position":2,"is_corresponding":false},{"id":258825,"name":"Kiran Musunuru","orcid":"0000-0003-3298-0368","position":3,"is_corresponding":false},{"id":368519,"name":"Rebecca C. Ahrens‐Nicklas","orcid":"0000-0001-8243-7123","position":4,"is_corresponding":false},{"id":29913,"name":"Xiao Wang","orcid":"0000-0002-3090-9894","position":5,"is_corresponding":false},{"id":721299,"name":"Dominique L. Brooks","orcid":null,"position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:07:42.497873Z","pmid":"37924808","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":[]}