Human recombinant palmitoyl-protein thioesterase-1 (PPT1) for preclinical evaluation of enzyme replacement therapy for infantile neuronal ceroid lipofuscinosis

Jui Yun Lu, Jie Hu, Sandra L. Hofmann

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Infantile neuronal ceroid lipofuscinosis (INCL, also known as Haltia-Santavuori disease) is a lysosomal storage disorder of infants and children characterized by blindness, seizures and a progressive neurodegenerative course. Recent clinical trials have involved neural stem cells and gene therapy directed to the central nervous system; however, enzyme replacement therapy has never been addressed. In the current paper, we describe the production of human recombinant PPT1 (the defective enzyme in INCL) by standard methods in Chinese Hamster Ovary (CHO) cells. The enzyme is largely mannose 6-phosphorylated as assessed by mannose 6-phosphate receptor binding (80% bound) and taken up rapidly by immortalized patient lymphoblasts, where clearance of PPT substrates was demonstrated (EC50 of 0.25 nM after overnight incubation). When injected intravenously into PPT1-deficient mice, the clearance of recombinant human PPT1 from plasma was rapid, with a half-life of 10 min. Most of the injected dose was distributed to the kidney and liver and potentially corrective levels were also observed in heart, lung and spleen. Brain uptake was minimal, as expected based on experience with other intravenously administered lysosomal enzymes. The enzyme may be useful as an adjunct to central nervous system-directed therapies and could be used as a starting point for modifications designed to improve brain delivery.

Original languageEnglish (US)
Pages (from-to)374-378
Number of pages5
JournalMolecular Genetics and Metabolism
Volume99
Issue number4
DOIs
StatePublished - Apr 2010

Fingerprint

Ceroid
Neuronal Ceroid-Lipofuscinoses
Enzyme Replacement Therapy
Recombinant Proteins
Enzymes
Neurology
Central Nervous System
IGF Type 2 Receptor
Brain
Neural Stem Cells
Blindness
Mannose
Cell- and Tissue-Based Therapy
Gene therapy
Cricetulus
Genetic Therapy
Half-Life
Ovary
Seizures
Stem cells

Keywords

  • Batten disease
  • Enzyme replacement therapy
  • Infantile neuronal ceroid lipofuscinosis
  • Lysosomal storage disorder

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{a106cfdec83b48f9a635323a9b36c3bc,
title = "Human recombinant palmitoyl-protein thioesterase-1 (PPT1) for preclinical evaluation of enzyme replacement therapy for infantile neuronal ceroid lipofuscinosis",
abstract = "Infantile neuronal ceroid lipofuscinosis (INCL, also known as Haltia-Santavuori disease) is a lysosomal storage disorder of infants and children characterized by blindness, seizures and a progressive neurodegenerative course. Recent clinical trials have involved neural stem cells and gene therapy directed to the central nervous system; however, enzyme replacement therapy has never been addressed. In the current paper, we describe the production of human recombinant PPT1 (the defective enzyme in INCL) by standard methods in Chinese Hamster Ovary (CHO) cells. The enzyme is largely mannose 6-phosphorylated as assessed by mannose 6-phosphate receptor binding (80{\%} bound) and taken up rapidly by immortalized patient lymphoblasts, where clearance of PPT substrates was demonstrated (EC50 of 0.25 nM after overnight incubation). When injected intravenously into PPT1-deficient mice, the clearance of recombinant human PPT1 from plasma was rapid, with a half-life of 10 min. Most of the injected dose was distributed to the kidney and liver and potentially corrective levels were also observed in heart, lung and spleen. Brain uptake was minimal, as expected based on experience with other intravenously administered lysosomal enzymes. The enzyme may be useful as an adjunct to central nervous system-directed therapies and could be used as a starting point for modifications designed to improve brain delivery.",
keywords = "Batten disease, Enzyme replacement therapy, Infantile neuronal ceroid lipofuscinosis, Lysosomal storage disorder",
author = "Lu, {Jui Yun} and Jie Hu and Hofmann, {Sandra L.}",
year = "2010",
month = "4",
doi = "10.1016/j.ymgme.2009.12.002",
language = "English (US)",
volume = "99",
pages = "374--378",
journal = "Molecular Genetics and Metabolism",
issn = "1096-7192",
publisher = "Academic Press Inc.",
number = "4",

}

TY - JOUR

T1 - Human recombinant palmitoyl-protein thioesterase-1 (PPT1) for preclinical evaluation of enzyme replacement therapy for infantile neuronal ceroid lipofuscinosis

AU - Lu, Jui Yun

AU - Hu, Jie

AU - Hofmann, Sandra L.

PY - 2010/4

Y1 - 2010/4

N2 - Infantile neuronal ceroid lipofuscinosis (INCL, also known as Haltia-Santavuori disease) is a lysosomal storage disorder of infants and children characterized by blindness, seizures and a progressive neurodegenerative course. Recent clinical trials have involved neural stem cells and gene therapy directed to the central nervous system; however, enzyme replacement therapy has never been addressed. In the current paper, we describe the production of human recombinant PPT1 (the defective enzyme in INCL) by standard methods in Chinese Hamster Ovary (CHO) cells. The enzyme is largely mannose 6-phosphorylated as assessed by mannose 6-phosphate receptor binding (80% bound) and taken up rapidly by immortalized patient lymphoblasts, where clearance of PPT substrates was demonstrated (EC50 of 0.25 nM after overnight incubation). When injected intravenously into PPT1-deficient mice, the clearance of recombinant human PPT1 from plasma was rapid, with a half-life of 10 min. Most of the injected dose was distributed to the kidney and liver and potentially corrective levels were also observed in heart, lung and spleen. Brain uptake was minimal, as expected based on experience with other intravenously administered lysosomal enzymes. The enzyme may be useful as an adjunct to central nervous system-directed therapies and could be used as a starting point for modifications designed to improve brain delivery.

AB - Infantile neuronal ceroid lipofuscinosis (INCL, also known as Haltia-Santavuori disease) is a lysosomal storage disorder of infants and children characterized by blindness, seizures and a progressive neurodegenerative course. Recent clinical trials have involved neural stem cells and gene therapy directed to the central nervous system; however, enzyme replacement therapy has never been addressed. In the current paper, we describe the production of human recombinant PPT1 (the defective enzyme in INCL) by standard methods in Chinese Hamster Ovary (CHO) cells. The enzyme is largely mannose 6-phosphorylated as assessed by mannose 6-phosphate receptor binding (80% bound) and taken up rapidly by immortalized patient lymphoblasts, where clearance of PPT substrates was demonstrated (EC50 of 0.25 nM after overnight incubation). When injected intravenously into PPT1-deficient mice, the clearance of recombinant human PPT1 from plasma was rapid, with a half-life of 10 min. Most of the injected dose was distributed to the kidney and liver and potentially corrective levels were also observed in heart, lung and spleen. Brain uptake was minimal, as expected based on experience with other intravenously administered lysosomal enzymes. The enzyme may be useful as an adjunct to central nervous system-directed therapies and could be used as a starting point for modifications designed to improve brain delivery.

KW - Batten disease

KW - Enzyme replacement therapy

KW - Infantile neuronal ceroid lipofuscinosis

KW - Lysosomal storage disorder

UR - http://www.scopus.com/inward/record.url?scp=77649337157&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77649337157&partnerID=8YFLogxK

U2 - 10.1016/j.ymgme.2009.12.002

DO - 10.1016/j.ymgme.2009.12.002

M3 - Article

C2 - 20036592

AN - SCOPUS:77649337157

VL - 99

SP - 374

EP - 378

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

SN - 1096-7192

IS - 4

ER -