Your browser doesn't support javascript.
loading
GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals.
Ter Huurne, Menno; Parker, Benjamin L; Liu, Ning Qing; Qian, Elizabeth Ling; Vivien, Celine; Karavendzas, Kathy; Mills, Richard J; Saville, Jennifer T; Abu-Bonsrah, Dad; Wise, Andrea F; Hudson, James E; Talbot, Andrew S; Finn, Patrick F; Martini, Paolo G V; Fuller, Maria; Ricardo, Sharon D; Watt, Kevin I; Nicholls, Kathy M; Porrello, Enzo R; Elliott, David A.
Afiliación
  • Ter Huurne M; 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, Au
  • Parker BL; Department of Anatomy and Physiology, University of Melbourne, Melbourne, VIC, Australia; Centre for Muscle Research, University of Melbourne, Melbourne, VIC, Australia.
  • Liu NQ; Department of Hematology, Erasmus Medical Center (MC) Cancer Institute, Rotterdam, the Netherlands.
  • Qian EL; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.
  • Vivien C; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.
  • Karavendzas K; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.
  • Mills RJ; 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, Austral
  • Saville JT; Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital and Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
  • Abu-Bonsrah D; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.
  • Wise AF; Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
  • Hudson JE; QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
  • Talbot AS; Department of Nephrology, The Royal Melbourne Hospital and Department of Medicine (RMH), University of Melbourne, Parkville, VIC, Australia.
  • Finn PF; Rare Diseases Research, Moderna Inc., 200 Technology Sq., Cambridge, MA, USA.
  • Martini PGV; Rare Diseases Research, Moderna Inc., 200 Technology Sq., Cambridge, MA, USA.
  • Fuller M; Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital and Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
  • Ricardo SD; Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
  • Watt KI; 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, Melbour
  • Nicholls KM; Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
  • Porrello ER; 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, Melbour
  • Elliott DA; 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
Am J Hum Genet ; 110(9): 1600-1605, 2023 09 07.
Article en En | MEDLINE | ID: mdl-37607539
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.
Asunto(s)
Palabras clave
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad de Fabry / Células Madre Pluripotentes Inducidas Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2023 Tipo del documento: Article País de afiliación: Australia
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad de Fabry / Células Madre Pluripotentes Inducidas Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2023 Tipo del documento: Article País de afiliación: Australia