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

Menno 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; David A Elliott

doi:10.1016/j.ajhg.2023.07.013

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

Am J Hum Genet. 2023 Sep 7;110(9):1600-1605. doi: 10.1016/j.ajhg.2023.07.013. Epub 2023 Aug 21.

Authors

Menno Ter Huurne¹, Benjamin L Parker², Ning Qing Liu³, Elizabeth Ling Qian⁴, Celine Vivien⁴, Kathy Karavendzas⁴, Richard J Mills⁵, Jennifer T Saville⁶, Dad Abu-Bonsrah⁴, Andrea F Wise⁷, James E Hudson⁸, Andrew S Talbot⁹, Patrick F Finn¹⁰, Paolo G V Martini¹⁰, Maria Fuller⁶, Sharon D Ricardo⁷, Kevin I Watt¹¹, Kathy M Nicholls⁷, Enzo R Porrello¹², David A Elliott¹³

Affiliations

¹ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia; The Novo Nordisk Foundation Centre for Stem Cell Medicine (reNEW), Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
² Department of Anatomy and Physiology, University of Melbourne, Melbourne, VIC, Australia; Centre for Muscle Research, University of Melbourne, Melbourne, VIC, Australia.
³ Department of Hematology, Erasmus Medical Center (MC) Cancer Institute, Rotterdam, the Netherlands.
⁴ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.
⁵ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia; The Novo Nordisk Foundation Centre for Stem Cell Medicine (reNEW), Murdoch Children's Research Institute, Melbourne, VIC, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4000, Australia.
⁶ Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital and Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
⁷ Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
⁸ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
⁹ Department of Nephrology, The Royal Melbourne Hospital and Department of Medicine (RMH), University of Melbourne, Parkville, VIC, Australia.
¹⁰ Rare Diseases Research, Moderna Inc., 200 Technology Sq., Cambridge, MA, USA.
¹¹ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia; The Novo Nordisk Foundation Centre for Stem Cell Medicine (reNEW), Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Anatomy and Physiology, University of Melbourne, Melbourne, VIC, Australia.
¹² Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia; The Novo Nordisk Foundation Centre for Stem Cell Medicine (reNEW), Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Anatomy and Physiology, University of Melbourne, Melbourne, VIC, Australia; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia. Electronic address: enzo.porrello@mcri.edu.au.
¹³ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia; The Novo Nordisk Foundation Centre for Stem Cell Medicine (reNEW), Murdoch Children's Research Institute, Melbourne, VIC, Australia; Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Australian Regenerative Medicine Institute (ARMI), Monash University, Clayton, VIC, Australia. Electronic address: david.elliott@mcri.edu.au.

Abstract

Recent 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.

Keywords: Fabry disease; lysosomal lumen proteins; nucleoside modified messenger RNA; patient iPSC-derived cardiomyocytes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Fabry Disease* / genetics
Fabry Disease* / therapy
Humans
Induced Pluripotent Stem Cells*
Myocytes, Cardiac
RNA
RNA, Messenger

Substances

RNA
RNA, Messenger