163482 20230915090522.0 10.1038/s41467-022-28080-7 doi pmid:35058465 pmid pmc:PMC8776779 pmc altmetric:121292945 altmetric DZNE-2022-00242 English 500 Lansing, Felix 0000-0001-9335-9749 0 Correction of a Factor VIII genomic inversion with designer-recombinases. [London] 2022 Nature Publishing Group UK article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1654869941_23357 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote Despite advances in nuclease-based genome editing technologies, correcting human disease-causing genomic inversions remains a challenge. Here, we describe the potential use of a recombinase-based system to correct the 140 kb inversion of the F8 gene frequently found in patients diagnosed with severe Hemophilia A. Employing substrate-linked directed molecular evolution, we develop a coupled heterodimeric recombinase system (RecF8) achieving 30% inversion of the target sequence in human tissue culture cells. Transient RecF8 treatment of endothelial cells, differentiated from patient-derived induced pluripotent stem cells (iPSCs) of a hemophilic donor, results in 12% correction of the inversion and restores Factor VIII mRNA expression. In this work, we present designer-recombinases as an efficient and specific means towards treatment of monogenic diseases caused by large gene inversions. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de Recombinases NLM Chemicals Factor VIII 9001-27-8 NLM Chemicals Amino Acid Sequence MeSH Base Sequence MeSH Cell Differentiation MeSH Chromosome Inversion: genetics MeSH Clone Cells MeSH Directed Molecular Evolution MeSH Endothelial Cells: cytology MeSH Endothelial Cells: metabolism MeSH Exons: genetics MeSH Factor VIII: genetics MeSH HEK293 Cells MeSH HeLa Cells MeSH Humans MeSH Induced Pluripotent Stem Cells: metabolism MeSH Inverted Repeat Sequences: genetics MeSH Recombinases: metabolism MeSH Recombination, Genetic: genetics MeSH Substrate Specificity MeSH Whole Genome Sequencing MeSH Mukhametzyanova, Liliya 1 Rojo-Romanos, Teresa 0000-0001-8660-9690 2 Iwasawa, Kentaro 3 Kimura, Masaki 4 Paszkowski-Rogacz, Maciej 0000-0002-8245-6006 5 Karpinski, Janet 6 Grass, Tobias P:(DE-2719)9000564 7 dzne Sonntag, Jan 8 Schneider, Paul Martin 0000-0001-5164-316X 9 Günes, Ceren 0000-0001-9475-9533 10 Hoersten, Jenna 0000-0002-1014-9859 11 Schmitt, Lukas Theo 0000-0002-5455-4901 12 Rodriguez-Muela, Natalia P:(DE-2719)9000726 13 dzne Knöfler, Ralf 14 Takebe, Takanori 0000-0002-6989-3041 15 Buchholz, Frank 0000-0002-4577-3344 16 10.1038/s41467-022-28080-7 Vol. 13, no. 1, p. 422 PERI:(DE-600)2553671-0 1 422 Nature Communications 13 2022 2041-1723 OpenAccess http://pub.dzne.de/record/163482/files/DZNE-2022-00242.pdf OpenAccess pdfa http://pub.dzne.de/record/163482/files/DZNE-2022-00242.pdf?subformat=pdfa oai:pub.dzne.de:163482 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 7 P:(DE-2719)9000564 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 13 P:(DE-2719)9000726 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 2022 Article Processing Charges StatID:(DE-HGF)0561 StatID 2021-02-02 Creative Commons Attribution CC BY (No Version) LIC:(DE-HGF)CCBYNV V:(DE-HGF) DOAJ 2021-02-02 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2021-02-02 Fees StatID:(DE-HGF)0700 StatID 2021-02-02 OpenAccess StatID:(DE-HGF)0510 StatID DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2021-02-02 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2021-02-02 JCR StatID:(DE-HGF)0100 StatID NAT COMMUN : 2021 2022-11-11 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2022-11-11 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2022-11-11 DBCoverage StatID:(DE-HGF)0501 StatID DOAJ Seal 2021-10-13T14:44:21Z DBCoverage StatID:(DE-HGF)0500 StatID DOAJ 2021-10-13T14:44:21Z Peer Review StatID:(DE-HGF)0030 StatID DOAJ : Peer review 2021-10-13T14:44:21Z DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2022-11-11 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2022-11-11 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2022-11-11 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2022-11-11 DBCoverage StatID:(DE-HGF)1040 StatID Zoological Record 2022-11-11 DBCoverage StatID:(DE-HGF)1060 StatID Current Contents - Agriculture, Biology and Environmental Sciences 2022-11-11 DBCoverage StatID:(DE-HGF)1150 StatID Current Contents - Physical, Chemical and Earth Sciences 2022-11-11 IF >= 15 StatID:(DE-HGF)9915 StatID NAT COMMUN : 2021 2022-11-11 I:(DE-2719)1713001 AG Rodriguez-Muela Selective Neuronal Vulnerability in Neurodegenerative Diseases 0 journal VDB UNRESTRICTED I:(DE-2719)1713001 FullTexts