Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the Receptor-associated Protein (RAP) and α-L-iduronidase or acid α-glucosidase

William S. Prince, Lynn M. McCormick, Dan J. Wendt, Paul A. Fitzpatrick, Keri L. Schwartz, Allora I. Aguilera, Vishwanath Koppaka, Terri M. Christianson, Michel C. Vellard, Nadine Pavloff, Jeff F. Lemontt, Minmin Qin, Chris M. Starr, Guojun D Bu, Todd C. Zankel

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Enzyme replacement therapy for lysosomal storage disorders depends on efficient uptake of recombinant enzyme into the tissues of patients. This uptake is mediated by oligosaccharide receptors including the cation-independent mannose 6-phosphate receptor and the mannose receptor. We have sought to exploit alternative receptor systems that are independent of glycosylation but allow for efficient delivery to the lysosome. Fusions of the human lysosomal enzymes α-L-iduronidase or acid α-glucosidase with the receptor-associated protein were efficiently endocytosed by lysosomal storage disorder patient fibroblasts, rat C6 glioma cells, mouse C2C12 myoblasts, and recombinant Chinese hamster ovary cells expressing individual members of the low-density lipoprotein receptor family. Uptake of the fusions exceeded that of phosphorylated enzyme in all cases, often by an order of magnitude or greater. Uptake was specifically mediated by members of the low-density lipoprotein receptor protein family and was followed by delivery of the fusions to the lysosome. The advantages of the lipoprotein receptor system over oligosaccharide receptor systems include more efficient cellular delivery and the potential for transcytosis of ligands across tight endothelia, including the blood-brain barrier.

Original languageEnglish (US)
Pages (from-to)35037-35046
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number33
DOIs
StatePublished - Aug 13 2004
Externally publishedYes

Fingerprint

Iduronidase
Lipoprotein Receptors
Glucosidases
Fusion reactions
LDL Receptors
Lysosomes
Oligosaccharides
Acids
Enzymes
IGF Type 2 Receptor
Enzyme Replacement Therapy
Transcytosis
Proteins
Myoblasts
Endocytosis
Cricetulus
Glycosylation
Blood-Brain Barrier
Glioma
Endothelium

ASJC Scopus subject areas

  • Biochemistry

Cite this

Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the Receptor-associated Protein (RAP) and α-L-iduronidase or acid α-glucosidase. / Prince, William S.; McCormick, Lynn M.; Wendt, Dan J.; Fitzpatrick, Paul A.; Schwartz, Keri L.; Aguilera, Allora I.; Koppaka, Vishwanath; Christianson, Terri M.; Vellard, Michel C.; Pavloff, Nadine; Lemontt, Jeff F.; Qin, Minmin; Starr, Chris M.; Bu, Guojun D; Zankel, Todd C.

In: Journal of Biological Chemistry, Vol. 279, No. 33, 13.08.2004, p. 35037-35046.

Research output: Contribution to journalArticle

Prince, WS, McCormick, LM, Wendt, DJ, Fitzpatrick, PA, Schwartz, KL, Aguilera, AI, Koppaka, V, Christianson, TM, Vellard, MC, Pavloff, N, Lemontt, JF, Qin, M, Starr, CM, Bu, GD & Zankel, TC 2004, 'Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the Receptor-associated Protein (RAP) and α-L-iduronidase or acid α-glucosidase', Journal of Biological Chemistry, vol. 279, no. 33, pp. 35037-35046. https://doi.org/10.1074/jbc.M402630200
Prince, William S. ; McCormick, Lynn M. ; Wendt, Dan J. ; Fitzpatrick, Paul A. ; Schwartz, Keri L. ; Aguilera, Allora I. ; Koppaka, Vishwanath ; Christianson, Terri M. ; Vellard, Michel C. ; Pavloff, Nadine ; Lemontt, Jeff F. ; Qin, Minmin ; Starr, Chris M. ; Bu, Guojun D ; Zankel, Todd C. / Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the Receptor-associated Protein (RAP) and α-L-iduronidase or acid α-glucosidase. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 33. pp. 35037-35046.
@article{f0407c969d8f46b39aa7c896ea34d539,
title = "Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the Receptor-associated Protein (RAP) and α-L-iduronidase or acid α-glucosidase",
abstract = "Enzyme replacement therapy for lysosomal storage disorders depends on efficient uptake of recombinant enzyme into the tissues of patients. This uptake is mediated by oligosaccharide receptors including the cation-independent mannose 6-phosphate receptor and the mannose receptor. We have sought to exploit alternative receptor systems that are independent of glycosylation but allow for efficient delivery to the lysosome. Fusions of the human lysosomal enzymes α-L-iduronidase or acid α-glucosidase with the receptor-associated protein were efficiently endocytosed by lysosomal storage disorder patient fibroblasts, rat C6 glioma cells, mouse C2C12 myoblasts, and recombinant Chinese hamster ovary cells expressing individual members of the low-density lipoprotein receptor family. Uptake of the fusions exceeded that of phosphorylated enzyme in all cases, often by an order of magnitude or greater. Uptake was specifically mediated by members of the low-density lipoprotein receptor protein family and was followed by delivery of the fusions to the lysosome. The advantages of the lipoprotein receptor system over oligosaccharide receptor systems include more efficient cellular delivery and the potential for transcytosis of ligands across tight endothelia, including the blood-brain barrier.",
author = "Prince, {William S.} and McCormick, {Lynn M.} and Wendt, {Dan J.} and Fitzpatrick, {Paul A.} and Schwartz, {Keri L.} and Aguilera, {Allora I.} and Vishwanath Koppaka and Christianson, {Terri M.} and Vellard, {Michel C.} and Nadine Pavloff and Lemontt, {Jeff F.} and Minmin Qin and Starr, {Chris M.} and Bu, {Guojun D} and Zankel, {Todd C.}",
year = "2004",
month = "8",
day = "13",
doi = "10.1074/jbc.M402630200",
language = "English (US)",
volume = "279",
pages = "35037--35046",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "33",

}

TY - JOUR

T1 - Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the Receptor-associated Protein (RAP) and α-L-iduronidase or acid α-glucosidase

AU - Prince, William S.

AU - McCormick, Lynn M.

AU - Wendt, Dan J.

AU - Fitzpatrick, Paul A.

AU - Schwartz, Keri L.

AU - Aguilera, Allora I.

AU - Koppaka, Vishwanath

AU - Christianson, Terri M.

AU - Vellard, Michel C.

AU - Pavloff, Nadine

AU - Lemontt, Jeff F.

AU - Qin, Minmin

AU - Starr, Chris M.

AU - Bu, Guojun D

AU - Zankel, Todd C.

PY - 2004/8/13

Y1 - 2004/8/13

N2 - Enzyme replacement therapy for lysosomal storage disorders depends on efficient uptake of recombinant enzyme into the tissues of patients. This uptake is mediated by oligosaccharide receptors including the cation-independent mannose 6-phosphate receptor and the mannose receptor. We have sought to exploit alternative receptor systems that are independent of glycosylation but allow for efficient delivery to the lysosome. Fusions of the human lysosomal enzymes α-L-iduronidase or acid α-glucosidase with the receptor-associated protein were efficiently endocytosed by lysosomal storage disorder patient fibroblasts, rat C6 glioma cells, mouse C2C12 myoblasts, and recombinant Chinese hamster ovary cells expressing individual members of the low-density lipoprotein receptor family. Uptake of the fusions exceeded that of phosphorylated enzyme in all cases, often by an order of magnitude or greater. Uptake was specifically mediated by members of the low-density lipoprotein receptor protein family and was followed by delivery of the fusions to the lysosome. The advantages of the lipoprotein receptor system over oligosaccharide receptor systems include more efficient cellular delivery and the potential for transcytosis of ligands across tight endothelia, including the blood-brain barrier.

AB - Enzyme replacement therapy for lysosomal storage disorders depends on efficient uptake of recombinant enzyme into the tissues of patients. This uptake is mediated by oligosaccharide receptors including the cation-independent mannose 6-phosphate receptor and the mannose receptor. We have sought to exploit alternative receptor systems that are independent of glycosylation but allow for efficient delivery to the lysosome. Fusions of the human lysosomal enzymes α-L-iduronidase or acid α-glucosidase with the receptor-associated protein were efficiently endocytosed by lysosomal storage disorder patient fibroblasts, rat C6 glioma cells, mouse C2C12 myoblasts, and recombinant Chinese hamster ovary cells expressing individual members of the low-density lipoprotein receptor family. Uptake of the fusions exceeded that of phosphorylated enzyme in all cases, often by an order of magnitude or greater. Uptake was specifically mediated by members of the low-density lipoprotein receptor protein family and was followed by delivery of the fusions to the lysosome. The advantages of the lipoprotein receptor system over oligosaccharide receptor systems include more efficient cellular delivery and the potential for transcytosis of ligands across tight endothelia, including the blood-brain barrier.

UR - http://www.scopus.com/inward/record.url?scp=4544321276&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4544321276&partnerID=8YFLogxK

U2 - 10.1074/jbc.M402630200

DO - 10.1074/jbc.M402630200

M3 - Article

VL - 279

SP - 35037

EP - 35046

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 33

ER -