Unravelling the mechanism of action of enzyme replacement therapy in Fabry disease

Younhee Ko, Cheol Ho Lee, Myeong Hee Moon, Geu Ru Hong, Chong Kun Cheon, Jin Sung Lee

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Fabry disease (FD) is a rare X-linked recessive glycosphingolipid-storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Intravenous enzyme replacement therapy (ERT) has been used to supplement deficient enzyme activity in patients with FD. Despite its clinical effect and manifestations, clear criteria for the clinical effectiveness and cost-effectiveness of ERT have not been well established. In this study, we investigated the pharmacodynamic actions and short-term effects of ERT in patients with FD through direct molecular profiling from blood samples of patients before and after ERT. Based on this comparison, we observed that immune/inflammation-related pathways and growth factor-related pathways such as innate/adaptive immune pathway, lymphocyte proliferation and leukocyte proliferation were actively regulated under ERT. We also found that TINAGL1, DAAM2, CDK5R1 and MYO5B known to be related with clinical symptoms of FD showed increased levels after ERT, leading to the amelioration of clinical manifestations. Especially the catabolic process-related genes, including USP15 and ERUN1, showed direct increasing after ERT in vivo in male patients. These results suggest that male patients with FD respond more actively to ERT than do female patients with FD. Pathway analysis revealed that oxidative phosphorylation pathway-related genes are downregulated under ERT. ERT has a role to protect the proteins from oxidative damage and such deactivation of oxidative phosphorylation is one of direct pharmacodynamic actions of ERT. These results extended our understanding of the pathophysiology of ERT. To our knowledge, this is the first study to observe the molecular basis for the mechanism of ERT in vivo through the comprehensive comparison of transcriptome study with next-generation sequencing data.

Original languageEnglish
Pages (from-to)143-149
Number of pages7
JournalJournal of human genetics
Volume61
Issue number2
DOIs
Publication statusPublished - 2016 Feb 1

Fingerprint

Enzyme Replacement Therapy
Fabry Disease
Oxidative Phosphorylation
alpha-Galactosidase
Glycosphingolipids
Enzymes
Transcriptome
Genes
Cost-Benefit Analysis

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Ko, Younhee ; Lee, Cheol Ho ; Moon, Myeong Hee ; Hong, Geu Ru ; Cheon, Chong Kun ; Lee, Jin Sung. / Unravelling the mechanism of action of enzyme replacement therapy in Fabry disease. In: Journal of human genetics. 2016 ; Vol. 61, No. 2. pp. 143-149.
@article{c9f1ec0d7653460a9957ba9b64ac9d78,
title = "Unravelling the mechanism of action of enzyme replacement therapy in Fabry disease",
abstract = "Fabry disease (FD) is a rare X-linked recessive glycosphingolipid-storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Intravenous enzyme replacement therapy (ERT) has been used to supplement deficient enzyme activity in patients with FD. Despite its clinical effect and manifestations, clear criteria for the clinical effectiveness and cost-effectiveness of ERT have not been well established. In this study, we investigated the pharmacodynamic actions and short-term effects of ERT in patients with FD through direct molecular profiling from blood samples of patients before and after ERT. Based on this comparison, we observed that immune/inflammation-related pathways and growth factor-related pathways such as innate/adaptive immune pathway, lymphocyte proliferation and leukocyte proliferation were actively regulated under ERT. We also found that TINAGL1, DAAM2, CDK5R1 and MYO5B known to be related with clinical symptoms of FD showed increased levels after ERT, leading to the amelioration of clinical manifestations. Especially the catabolic process-related genes, including USP15 and ERUN1, showed direct increasing after ERT in vivo in male patients. These results suggest that male patients with FD respond more actively to ERT than do female patients with FD. Pathway analysis revealed that oxidative phosphorylation pathway-related genes are downregulated under ERT. ERT has a role to protect the proteins from oxidative damage and such deactivation of oxidative phosphorylation is one of direct pharmacodynamic actions of ERT. These results extended our understanding of the pathophysiology of ERT. To our knowledge, this is the first study to observe the molecular basis for the mechanism of ERT in vivo through the comprehensive comparison of transcriptome study with next-generation sequencing data.",
author = "Younhee Ko and Lee, {Cheol Ho} and Moon, {Myeong Hee} and Hong, {Geu Ru} and Cheon, {Chong Kun} and Lee, {Jin Sung}",
year = "2016",
month = "2",
day = "1",
doi = "10.1038/jhg.2015.123",
language = "English",
volume = "61",
pages = "143--149",
journal = "Journal of Human Genetics",
issn = "1434-5161",
publisher = "Nature Publishing Group",
number = "2",

}

Unravelling the mechanism of action of enzyme replacement therapy in Fabry disease. / Ko, Younhee; Lee, Cheol Ho; Moon, Myeong Hee; Hong, Geu Ru; Cheon, Chong Kun; Lee, Jin Sung.

In: Journal of human genetics, Vol. 61, No. 2, 01.02.2016, p. 143-149.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Unravelling the mechanism of action of enzyme replacement therapy in Fabry disease

AU - Ko, Younhee

AU - Lee, Cheol Ho

AU - Moon, Myeong Hee

AU - Hong, Geu Ru

AU - Cheon, Chong Kun

AU - Lee, Jin Sung

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Fabry disease (FD) is a rare X-linked recessive glycosphingolipid-storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Intravenous enzyme replacement therapy (ERT) has been used to supplement deficient enzyme activity in patients with FD. Despite its clinical effect and manifestations, clear criteria for the clinical effectiveness and cost-effectiveness of ERT have not been well established. In this study, we investigated the pharmacodynamic actions and short-term effects of ERT in patients with FD through direct molecular profiling from blood samples of patients before and after ERT. Based on this comparison, we observed that immune/inflammation-related pathways and growth factor-related pathways such as innate/adaptive immune pathway, lymphocyte proliferation and leukocyte proliferation were actively regulated under ERT. We also found that TINAGL1, DAAM2, CDK5R1 and MYO5B known to be related with clinical symptoms of FD showed increased levels after ERT, leading to the amelioration of clinical manifestations. Especially the catabolic process-related genes, including USP15 and ERUN1, showed direct increasing after ERT in vivo in male patients. These results suggest that male patients with FD respond more actively to ERT than do female patients with FD. Pathway analysis revealed that oxidative phosphorylation pathway-related genes are downregulated under ERT. ERT has a role to protect the proteins from oxidative damage and such deactivation of oxidative phosphorylation is one of direct pharmacodynamic actions of ERT. These results extended our understanding of the pathophysiology of ERT. To our knowledge, this is the first study to observe the molecular basis for the mechanism of ERT in vivo through the comprehensive comparison of transcriptome study with next-generation sequencing data.

AB - Fabry disease (FD) is a rare X-linked recessive glycosphingolipid-storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Intravenous enzyme replacement therapy (ERT) has been used to supplement deficient enzyme activity in patients with FD. Despite its clinical effect and manifestations, clear criteria for the clinical effectiveness and cost-effectiveness of ERT have not been well established. In this study, we investigated the pharmacodynamic actions and short-term effects of ERT in patients with FD through direct molecular profiling from blood samples of patients before and after ERT. Based on this comparison, we observed that immune/inflammation-related pathways and growth factor-related pathways such as innate/adaptive immune pathway, lymphocyte proliferation and leukocyte proliferation were actively regulated under ERT. We also found that TINAGL1, DAAM2, CDK5R1 and MYO5B known to be related with clinical symptoms of FD showed increased levels after ERT, leading to the amelioration of clinical manifestations. Especially the catabolic process-related genes, including USP15 and ERUN1, showed direct increasing after ERT in vivo in male patients. These results suggest that male patients with FD respond more actively to ERT than do female patients with FD. Pathway analysis revealed that oxidative phosphorylation pathway-related genes are downregulated under ERT. ERT has a role to protect the proteins from oxidative damage and such deactivation of oxidative phosphorylation is one of direct pharmacodynamic actions of ERT. These results extended our understanding of the pathophysiology of ERT. To our knowledge, this is the first study to observe the molecular basis for the mechanism of ERT in vivo through the comprehensive comparison of transcriptome study with next-generation sequencing data.

UR - http://www.scopus.com/inward/record.url?scp=84959306362&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959306362&partnerID=8YFLogxK

U2 - 10.1038/jhg.2015.123

DO - 10.1038/jhg.2015.123

M3 - Article

C2 - 26490183

AN - SCOPUS:84959306362

VL - 61

SP - 143

EP - 149

JO - Journal of Human Genetics

JF - Journal of Human Genetics

SN - 1434-5161

IS - 2

ER -