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

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^*

^*Corresponding author for this work

Hematology

Royal Children's Hospital Melbourne
Murdoch Children's Research Institute
University of Melbourne
Queensland Institute of Medical Research
Queensland University of Technology
University of Adelaide
Monash University
Moderna Therapeutics

Research output: Contribution to journal › Article › Academic › peer-review

13 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	1600-1605
Number of pages	6
Journal	American Journal of Human Genetics
Volume	110
Issue number	9
DOIs	https://doi.org/10.1016/j.ajhg.2023.07.013
Publication status	Published - 7 Sept 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

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GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individualsFinal published version, 2.91 MBLicence: CC BY-NC-ND

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ter Huurne, M., Parker, B. L., Liu, N. Q., Qian, E. L., Vivien, C., Karavendzas, K., Mills, R. J., Saville, J. T., Abu-Bonsrah, D., Wise, A. F., Hudson, J. E., Talbot, A. S., Finn, P. F., Martini, P. G. V., Fuller, M., Ricardo, S. D., Watt, K. I., Nicholls, K. M., Porrello, E. R., & Elliott, D. A. (2023). GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals. American Journal of Human Genetics, 110(9), 1600-1605. https://doi.org/10.1016/j.ajhg.2023.07.013

@article{d395672b3f6b4ce2bd606da10a115e19,

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

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.",

author = "\{ter Huurne\}, Menno and Parker, \{Benjamin L.\} and Liu, \{Ning Qing\} and Qian, \{Elizabeth Ling\} and Celine Vivien and Kathy Karavendzas and Mills, \{Richard J.\} and Saville, \{Jennifer T.\} and Dad Abu-Bonsrah and Wise, \{Andrea F.\} and Hudson, \{James E.\} and Talbot, \{Andrew S.\} and Finn, \{Patrick F.\} and Martini, \{Paolo G.V.\} and Maria Fuller and Ricardo, \{Sharon D.\} and Watt, \{Kevin I.\} and Nicholls, \{Kathy M.\} and Porrello, \{Enzo R.\} and Elliott, \{David A.\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = sep,

day = "7",

doi = "10.1016/j.ajhg.2023.07.013",

language = "English",

volume = "110",

pages = "1600--1605",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "9",

}

ter Huurne, M, Parker, BL, Liu, NQ, Qian, EL, Vivien, C, Karavendzas, K, Mills, RJ, Saville, JT, Abu-Bonsrah, D, Wise, AF, Hudson, JE, Talbot, AS, Finn, PF, Martini, PGV, Fuller, M, Ricardo, SD, Watt, KI, Nicholls, KM, Porrello, ER & Elliott, DA 2023, 'GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals', American Journal of Human Genetics, vol. 110, no. 9, pp. 1600-1605. https://doi.org/10.1016/j.ajhg.2023.07.013

TY - JOUR

T1 - GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals

AU - ter Huurne, Menno

AU - Parker, Benjamin L.

AU - Liu, Ning Qing

AU - Qian, Elizabeth Ling

AU - Vivien, Celine

AU - Karavendzas, Kathy

AU - Mills, Richard J.

AU - Saville, Jennifer T.

AU - Abu-Bonsrah, Dad

AU - Wise, Andrea F.

AU - Hudson, James E.

AU - Talbot, Andrew S.

AU - Finn, Patrick F.

AU - Martini, Paolo G.V.

AU - Fuller, Maria

AU - Ricardo, Sharon D.

AU - Watt, Kevin I.

AU - Nicholls, Kathy M.

AU - Porrello, Enzo R.

AU - Elliott, David A.

PY - 2023/9/7

Y1 - 2023/9/7

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85170076908

U2 - 10.1016/j.ajhg.2023.07.013

DO - 10.1016/j.ajhg.2023.07.013

M3 - Article

C2 - 37607539

AN - SCOPUS:85170076908

SN - 0002-9297

VL - 110

SP - 1600

EP - 1605

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 9

ER -

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

Abstract

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