GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals

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dc.contributor.authorter Huurne, M.
dc.contributor.authorParker, B.L.
dc.contributor.authorLiu, N.Q.
dc.contributor.authorQian, E.L.
dc.contributor.authorVivien, C.
dc.contributor.authorKaravendzas, K.
dc.contributor.authorMills, R.J.
dc.contributor.authorSaville, J.T.
dc.contributor.authorAbu-Bonsrah, D.
dc.contributor.authorWise, A.F.
dc.contributor.authorHudson, J.E.
dc.contributor.authorTalbot, A.S.
dc.contributor.authorFinn, P.F.
dc.contributor.authorMartini, P.G.V.
dc.contributor.authorFuller, M.
dc.contributor.authorRicardo, S.D.
dc.contributor.authorWatt, K.I.
dc.contributor.authorNicholls, K.M.
dc.contributor.authorPorrello, E.R.
dc.contributor.authorElliott, D.A.
dc.date.issued2023
dc.descriptionPublished: August 21, 2023
dc.description.abstractRecent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the galactosidase alpha (GLA), which codes for α-Galactosidase A (α-GAL) enzyme, in a human cardiac model generated from induced pluripotent stem cells (iPSCs) derived from two individuals with Fabry disease. Consistent with the clinical phenotype, cardiomyocytes from iPSCs derived from Fabry-affected individuals showed accumulation of the glycosphingolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate. Furthermore, the Fabry cardiomyocytes displayed significant upregulation of lysosomal-associated proteins. Upon GLA modRNA treatment, a subset of lysosomal proteins were partially restored to wild-type levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA-treated cardiomyocytes, demonstrating that α-GAL enzymatic activity was restored. Together, our results validate the utility of iPSC-derived cardiomyocytes from affected individuals as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart.
dc.description.statementofresponsibilityMenno ter Huurne, Benjamin L. Parker, Ning Qing Liu, Elizabeth Ling Qian, Celine Vivien, Kathy Karavendzas, Richard J. Mills, Jennifer T. Saville, Dad Abu-Bonsrah, Andrea F. Wise, James E. Hudson, Andrew S. Talbot, Patrick F. Finn, Paolo G.V. Martini, Maria Fuller, Sharon D. Ricardo, Kevin I. Watt, Kathy M. Nicholls, Enzo R. Porrello, and David A. Elliott
dc.identifier.citationAmerican Journal of Human Genetics, 2023; 110(9):1600-1605
dc.identifier.doi10.1016/j.ajhg.2023.07.013
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.orcidSaville, J.T. [0000-0002-1401-314X]
dc.identifier.orcidFuller, M. [0000-0001-9092-8942]
dc.identifier.urihttps://hdl.handle.net/2440/139761
dc.language.isoen
dc.publisherElsevier (Cell Press)
dc.relation.grantARC
dc.rights© 2023 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
dc.source.urihttps://doi.org/10.1016/j.ajhg.2023.07.013
dc.subjectFabry Disease
dc.subject.meshMyocytes, Cardiac
dc.subject.meshHumans
dc.subject.meshFabry Disease
dc.subject.meshRNA
dc.subject.meshRNA, Messenger
dc.subject.meshInduced Pluripotent Stem Cells
dc.titleGLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals
dc.typeJournal article
pubs.publication-statusPublished

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