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In vivo adenine base editing rescues adrenoleukodystrophy in a humanized mouse model

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dc.contributor.authorRamu Gopalappa-
dc.contributor.authorMinYoung Lee-
dc.contributor.authorGlobinna Kim-
dc.contributor.authorEul Sik Jung-
dc.contributor.authorHanahrae Lee-
dc.contributor.authorHye-Yeon Hwang-
dc.contributor.authorJong Geol Lee-
dc.contributor.authorSu Jung Kim-
dc.contributor.authorHyun Ju Yoo-
dc.contributor.authorYoung Hoon Sung-
dc.contributor.authorDaesik Kim-
dc.contributor.authorIn-Jeoung Baek-
dc.contributor.authorHyongbum Henry Kim-
dc.date.accessioned2024-07-18T05:50:01Z-
dc.date.available2024-07-18T05:50:01Z-
dc.date.created2024-06-18-
dc.date.issued2024-07-
dc.identifier.issn1525-0016-
dc.identifier.urihttps://pr.ibs.re.kr/handle/8788114/15373-
dc.description.abstractX-linked adrenoleukodystrophy (ALD), an inherited neurometabolic disorder caused by mutations in ABCD1, which encodes the peroxisomal ABC transporter, mainly affects the brain, spinal cord, adrenal glands, and testes. In ALD patients, very-long-chain fatty acids (VLCFAs) fail to enter the peroxisome and undergo subsequent β-oxidation, resulting in their accumulation in the body. It has not been tested whether in vivo base editing or prime editing can be harnessed to ameliorate ALD. We developed a humanized mouse model of ALD by inserting a human cDNA containing the pathogenic variant into the mouse Abcd1 locus. The humanized ALD model showed increased levels of VLCFAs. To correct the mutation, we tested both base editing and prime editing and found that base editing using ABE8e(V106W) could correct the mutation in patient-derived fibroblasts at an efficiency of 7.4%. Adeno-associated virus (AAV)-mediated systemic delivery of NG-ABE8e(V106W) enabled robust correction of the pathogenic variant in the mouse brain (correction efficiency: ∼5.5%), spinal cord (∼5.1%), and adrenal gland (∼2%), leading to a significant reduction in the plasma levels of C26:0/C22:0. This established humanized mouse model and the successful correction of the pathogenic variant using a base editor serve as a significant step toward treating human ALD disease. © 2024 The American Society of Gene and Cell Therapy-
dc.language영어-
dc.publisherNature Publishing Group-
dc.titleIn vivo adenine base editing rescues adrenoleukodystrophy in a humanized mouse model-
dc.typeArticle-
dc.type.rimsART-
dc.identifier.wosid001265386200001-
dc.identifier.scopusid2-s2.0-85195409813-
dc.identifier.rimsid83268-
dc.contributor.affiliatedAuthorHyongbum Henry Kim-
dc.identifier.doi10.1016/j.ymthe.2024.05.027-
dc.identifier.bibliographicCitationMolecular Therapy, v.32, no.7, pp.2190 - 2206-
dc.relation.isPartOfMolecular Therapy-
dc.citation.titleMolecular Therapy-
dc.citation.volume32-
dc.citation.number7-
dc.citation.startPage2190-
dc.citation.endPage2206-
dc.description.journalClass1-
dc.description.journalClass1-
dc.description.isOpenAccessN-
dc.description.journalRegisteredClassscie-
dc.description.journalRegisteredClassscopus-
dc.subject.keywordAuthorABCD1-
dc.subject.keywordAuthoradenine base editing-
dc.subject.keywordAuthoradrenoleukodystrophy-
dc.subject.keywordAuthorCRISPR-
dc.subject.keywordAuthorgenome editing-
dc.subject.keywordAuthorhumanized mouse model-
dc.subject.keywordAuthorvery-long-chain fatty acid-
Appears in Collections:
Center for Nanomedicine (나노의학 연구단) > 1. Journal Papers (저널논문)
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