LPA disruption with AAV-CRISPR potently lowers plasma apo(a) in transgenic mouse model: A proof-of-concept study

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dc.citation.firstpage337en_US
dc.citation.journalTitleMolecular Therapy - Methods & Clinical Developmenten_US
dc.citation.lastpage351en_US
dc.citation.volumeNumber27en_US
dc.contributor.authorDoerfler, Alexandria M.en_US
dc.contributor.authorPark, So Hyunen_US
dc.contributor.authorAssini, Julia M.en_US
dc.contributor.authorYoussef, Ameren_US
dc.contributor.authorSaxena, Lavanyaen_US
dc.contributor.authorYaseen, Adam B.en_US
dc.contributor.authorDe Giorgi, Marcoen_US
dc.contributor.authorChuecos, Marcelen_US
dc.contributor.authorHurley, Ayrea E.en_US
dc.contributor.authorLi, Angen_US
dc.contributor.authorMarcovina, Santica M.en_US
dc.contributor.authorBao, Gangen_US
dc.contributor.authorBoffa, Michael B.en_US
dc.contributor.authorKoschinsky, Marlys L.en_US
dc.contributor.authorLagor, William R.en_US
dc.contributor.orgBioengineeringen_US
dc.date.accessioned2022-12-13T19:11:07Zen_US
dc.date.available2022-12-13T19:11:07Zen_US
dc.date.issued2022en_US
dc.description.abstractLipoprotein(a) (Lp(a)) represents a unique subclass of circulating lipoprotein particles and consists of an apolipoprotein(a) (apo(a)) molecule covalently bound to apolipoprotein B-100. The metabolism of Lp(a) particles is distinct from that of low-density lipoprotein (LDL) cholesterol, and currently approved lipid-lowering drugs do not provide substantial reductions in Lp(a), a causal risk factor for cardiovascular disease. Somatic genome editing has the potential to be a one-time therapy for individuals with extremely high Lp(a). We generated an LPA transgenic mouse model expressing apo(a) of physiologically relevant size. Adeno-associated virus (AAV) vector delivery of CRISPR-Cas9 was used to disrupt the LPA transgene in the liver. AAV-CRISPR nearly completely eliminated apo(a) from the circulation within a week. We performed genome-wide off-target assays to determine the specificity of CRISPR-Cas9 editing within the context of the human genome. Interestingly, we identified intrachromosomal rearrangements within the LPA cDNA in the transgenic mice as well as in the LPA gene in HEK293T cells, due to the repetitive sequences within LPA itself and neighboring pseudogenes. This proof-of-concept study establishes the feasibility of using CRISPR-Cas9 to disrupt LPA in vivo, and highlights the importance of examining the diverse consequences of CRISPR cutting within repetitive loci and in the genome globally.en_US
dc.identifier.citationDoerfler, Alexandria M., Park, So Hyun, Assini, Julia M., et al.. "LPA disruption with AAV-CRISPR potently lowers plasma apo(a) in transgenic mouse model: A proof-of-concept study." <i>Molecular Therapy - Methods & Clinical Development,</i> 27, (2022) Elsevier: 337-351. https://doi.org/10.1016/j.omtm.2022.10.009.en_US
dc.identifier.digital1-s2-0-S2329050122001516-mainen_US
dc.identifier.doihttps://doi.org/10.1016/j.omtm.2022.10.009en_US
dc.identifier.urihttps://hdl.handle.net/1911/114078en_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.titleLPA disruption with AAV-CRISPR potently lowers plasma apo(a) in transgenic mouse model: A proof-of-concept studyen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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