Targeting the Apoa1 locus for liver-directed gene therapy

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dc.citation.firstpage656
dc.citation.journalTitleMolecular Therapy - Methods & Clinical Development
dc.citation.lastpage669
dc.citation.volumeNumber21
dc.contributor.authorDe Giorgi, Marco
dc.contributor.authorLi, Ang
dc.contributor.authorHurley, Ayrea
dc.contributor.authorBarzi, Mercedes
dc.contributor.authorDoerfler, Alexandria M.
dc.contributor.authorCherayil, Nikitha A.
dc.contributor.authorSmith, Harrison E.
dc.contributor.authorBrown, Jonathan D.
dc.contributor.authorLin, Charles Y.
dc.contributor.authorBissig, Karl-Dimiter
dc.contributor.authorBao, Gang
dc.contributor.authorLagor, William R.
dc.date.accessioned2021-06-10T17:36:47Z
dc.date.available2021-06-10T17:36:47Z
dc.date.issued2021
dc.description.abstractClinical application of somatic genome editing requires therapeutics that are generalizable to a broad range of patients. Targeted insertion of promoterless transgenes can ensure that edits are permanent and broadly applicable while minimizing risks of off-target integration. In the liver, the Albumin (Alb) locus is currently the only well-characterized site for promoterless transgene insertion. Here, we target the Apoa1 locus with adeno-associated viral (AAV) delivery of CRISPR-Cas9 and achieve rates of 6% to 16% of targeted hepatocytes, with no evidence of toxicity. We further show that the endogenous Apoa1 promoter can drive robust and sustained expression of therapeutic proteins, such as apolipoprotein E (APOE), dramatically reducing plasma lipids in a model of hypercholesterolemia. Finally, we demonstrate that Apoa1-targeted fumarylacetoacetate hydrolase (FAH) can correct and rescue the severe metabolic liver disease hereditary tyrosinemia type I. In summary, we identify and validate Apoa1 as a novel integration site that supports durable transgene expression in the liver for gene therapy applications.
dc.identifier.citationDe Giorgi, Marco, Li, Ang, Hurley, Ayrea, et al.. "Targeting the Apoa1 locus for liver-directed gene therapy." <i>Molecular Therapy - Methods & Clinical Development,</i> 21, (2021) Cell Press: 656-669. https://doi.org/10.1016/j.omtm.2021.04.011.
dc.identifier.digital1-s2-0-S2329050121000772-main
dc.identifier.doihttps://doi.org/10.1016/j.omtm.2021.04.011
dc.identifier.urihttps://hdl.handle.net/1911/110709
dc.language.isoeng
dc.publisherCell Press
dc.rightsThis is an open access article under the CC BY-NC-ND license
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleTargeting the Apoa1 locus for liver-directed gene therapy
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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