{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Cancellieri S"],"funding":["Doris Duke Charitable Foundation","Burroughs Wellcome Fund","NHLBI NIH HHS","St. Jude Children’s Research Hospital","NHGRI NIH HHS","U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute","U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute"],"pagination":["34-43"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10272994"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["55(1)"],"pubmed_abstract":["CRISPR gene editing holds great promise to modify DNA sequences in somatic cells to treat disease. However, standard computational and biochemical methods to predict off-target potential focus on reference genomes. We developed an efficient tool called CRISPRme that considers single-nucleotide polymorphism (SNP) and indel genetic variants to nominate and prioritize off-target sites. We tested the software with a BCL11A enhancer targeting guide RNA (gRNA) showing promise in clinical trials for sickle cell disease and β-thalassemia and found that the top candidate off-target is produced by an allele common in African-ancestry populations (MAF 4.5%) that introduces a protospacer adjacent motif (PAM) sequence. We validated that SpCas9 generates strictly allele-specific indels and pericentric i"],"journal":["Nature genetics"],"pubmed_title":["Human genetic diversity alters off-target outcomes of therapeutic gene editing."],"pmcid":["PMC10272994"],"funding_grant_id":["R35 HG010717","P01HL053749","P01 HL053749","OT2 HL154984","RM1 HG009490","R35HG010717","RM1HG009490","OT2HL154984"],"pubmed_authors":["Giugno R","Pinello L","Armant M","Nguyen MA","Wolfe SA","Bauer DE","Bombieri N","Cancellieri S","Katta V","Tognon M","Lin LY","Zeng J","Tsai SQ","Lin J","Ciuculescu MF","Maitland SA"],"additional_accession":[]},"is_claimable":false,"name":"Human genetic diversity alters off-target outcomes of therapeutic gene editing.","description":"CRISPR gene editing holds great promise to modify DNA sequences in somatic cells to treat disease. However, standard computational and biochemical methods to predict off-target potential focus on reference genomes. We developed an efficient tool called CRISPRme that considers single-nucleotide polymorphism (SNP) and indel genetic variants to nominate and prioritize off-target sites. We tested the software with a BCL11A enhancer targeting guide RNA (gRNA) showing promise in clinical trials for sickle cell disease and β-thalassemia and found that the top candidate off-target is produced by an allele common in African-ancestry populations (MAF 4.5%) that introduces a protospacer adjacent motif (PAM) sequence. We validated that SpCas9 generates strictly allele-specific indels and pericentric i","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jan","modification":"2026-04-29T02:37:59.798Z","creation":"2024-11-09T00:25:01.848Z"},"accession":"S-EPMC10272994","cross_references":{"pubmed":["36522432"],"doi":["10.1038/s41588-022-01257-y"]}}