In vivo genome editing at the albumin locus to treat methylmalonic acidemia

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dc.citation.firstpage619en_US
dc.citation.journalTitleMolecular Therapy - Methods & Clinical Developmenten_US
dc.citation.lastpage632en_US
dc.citation.volumeNumber23en_US
dc.contributor.authorSchneller, Jessica L.en_US
dc.contributor.authorLee, Ciaran M.en_US
dc.contributor.authorVenturoni, Leah E.en_US
dc.contributor.authorChandler, Randy J.en_US
dc.contributor.authorLi, Angen_US
dc.contributor.authorMyung, Sanghoen_US
dc.contributor.authorCradick, Thomas J.en_US
dc.contributor.authorHurley, Ayrea E.en_US
dc.contributor.authorLagor, William R.en_US
dc.contributor.authorBao, Gangen_US
dc.contributor.authorVenditti, Charles P.en_US
dc.contributor.orgBioengineeringen_US
dc.date.accessioned2021-12-15T22:10:15Zen_US
dc.date.available2021-12-15T22:10:15Zen_US
dc.date.issued2021en_US
dc.description.abstractMethylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5′ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed.en_US
dc.identifier.citationSchneller, Jessica L., Lee, Ciaran M., Venturoni, Leah E., et al.. "In vivo genome editing at the albumin locus to treat methylmalonic acidemia." <i>Molecular Therapy - Methods & Clinical Development,</i> 23, (2021) Elsevier: 619-632. https://doi.org/10.1016/j.omtm.2021.11.004.en_US
dc.identifier.digital1-s2-0-S2329050121001765-mainen_US
dc.identifier.doihttps://doi.org/10.1016/j.omtm.2021.11.004en_US
dc.identifier.urihttps://hdl.handle.net/1911/111787en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).en_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/).en_US
dc.titleIn vivo genome editing at the albumin locus to treat methylmalonic acidemiaen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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