Chronic Enzyme Replacement to the Brain of a Late Infantile Neuronal Ceroid Lipofuscinosis Mouse Has Differential Effects on Phenotypes of Disease

Jennifer A. Wiseman, Yu Meng, Yuliya Nemtsova, Paul G. Matteson, James Millonig, Dirk Moore, David E. Sleat, Peter Lobel

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal inherited neurodegenerative disease caused by loss of lysosomal protease tripeptidyl peptidase 1 (TPP1). We have investigated the effects of chronic intrathecal (IT) administration using enzyme replacement therapy (ERT) to the brain of an LINCL mouse model, in which locomotor function declines dramatically prior to early death. Median lifespan was significantly extended from 126 days to >259 days when chronic IT treatment was initiated before the onset of disease. While treated animals lived longer and showed little sign of locomotor dysfunction as measured by stride length, some or all (depending on regimen) still died prematurely. One explanation is that cerebrospinal fluid (CSF)-mediated delivery may not deliver TPP1 to all brain regions. Morphological studies support this, showing delivery of TPP1 to ventral, but not deeper and dorsal regions. When IT treatment is initiated in severely affected LINCL mice, lifespan was extended modestly in most but dramatically extended in approximately one-third of the cohort. Treatment improved locomotor function in these severely compromised animals after it had declined to the point at which animals normally die. This indicates that some pathology in LINCL is reversible and does not simply reflect neuronal death.

Original languageEnglish (US)
Pages (from-to)204-212
Number of pages9
JournalMolecular Therapy - Methods and Clinical Development
Volume4
DOIs
StatePublished - Mar 17 2017

Fingerprint

Neuronal Ceroid-Lipofuscinoses
Phenotype
Brain
Enzymes
Enzyme Replacement Therapy
Neurodegenerative Diseases
Cerebrospinal Fluid
Peptide Hydrolases
Therapeutics
Pathology
tripeptidyl-peptidase 1

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Keywords

  • chronic
  • enzyme replacement therapy
  • intrathecal
  • neuronal ceroid lipofuscinosis
  • tripeptidyl peptidase 1

Cite this

@article{0c291f3db2d04d559f62705dab3eda40,
title = "Chronic Enzyme Replacement to the Brain of a Late Infantile Neuronal Ceroid Lipofuscinosis Mouse Has Differential Effects on Phenotypes of Disease",
abstract = "Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal inherited neurodegenerative disease caused by loss of lysosomal protease tripeptidyl peptidase 1 (TPP1). We have investigated the effects of chronic intrathecal (IT) administration using enzyme replacement therapy (ERT) to the brain of an LINCL mouse model, in which locomotor function declines dramatically prior to early death. Median lifespan was significantly extended from 126 days to >259 days when chronic IT treatment was initiated before the onset of disease. While treated animals lived longer and showed little sign of locomotor dysfunction as measured by stride length, some or all (depending on regimen) still died prematurely. One explanation is that cerebrospinal fluid (CSF)-mediated delivery may not deliver TPP1 to all brain regions. Morphological studies support this, showing delivery of TPP1 to ventral, but not deeper and dorsal regions. When IT treatment is initiated in severely affected LINCL mice, lifespan was extended modestly in most but dramatically extended in approximately one-third of the cohort. Treatment improved locomotor function in these severely compromised animals after it had declined to the point at which animals normally die. This indicates that some pathology in LINCL is reversible and does not simply reflect neuronal death.",
keywords = "chronic, enzyme replacement therapy, intrathecal, neuronal ceroid lipofuscinosis, tripeptidyl peptidase 1",
author = "Wiseman, {Jennifer A.} and Yu Meng and Yuliya Nemtsova and Matteson, {Paul G.} and James Millonig and Dirk Moore and Sleat, {David E.} and Peter Lobel",
year = "2017",
month = "3",
day = "17",
doi = "10.1016/j.omtm.2017.01.004",
language = "English (US)",
volume = "4",
pages = "204--212",
journal = "Molecular Therapy - Methods and Clinical Development",
issn = "2329-0501",
publisher = "Nature Publishing Group",

}

Chronic Enzyme Replacement to the Brain of a Late Infantile Neuronal Ceroid Lipofuscinosis Mouse Has Differential Effects on Phenotypes of Disease. / Wiseman, Jennifer A.; Meng, Yu; Nemtsova, Yuliya; Matteson, Paul G.; Millonig, James; Moore, Dirk; Sleat, David E.; Lobel, Peter.

In: Molecular Therapy - Methods and Clinical Development, Vol. 4, 17.03.2017, p. 204-212.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Chronic Enzyme Replacement to the Brain of a Late Infantile Neuronal Ceroid Lipofuscinosis Mouse Has Differential Effects on Phenotypes of Disease

AU - Wiseman, Jennifer A.

AU - Meng, Yu

AU - Nemtsova, Yuliya

AU - Matteson, Paul G.

AU - Millonig, James

AU - Moore, Dirk

AU - Sleat, David E.

AU - Lobel, Peter

PY - 2017/3/17

Y1 - 2017/3/17

N2 - Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal inherited neurodegenerative disease caused by loss of lysosomal protease tripeptidyl peptidase 1 (TPP1). We have investigated the effects of chronic intrathecal (IT) administration using enzyme replacement therapy (ERT) to the brain of an LINCL mouse model, in which locomotor function declines dramatically prior to early death. Median lifespan was significantly extended from 126 days to >259 days when chronic IT treatment was initiated before the onset of disease. While treated animals lived longer and showed little sign of locomotor dysfunction as measured by stride length, some or all (depending on regimen) still died prematurely. One explanation is that cerebrospinal fluid (CSF)-mediated delivery may not deliver TPP1 to all brain regions. Morphological studies support this, showing delivery of TPP1 to ventral, but not deeper and dorsal regions. When IT treatment is initiated in severely affected LINCL mice, lifespan was extended modestly in most but dramatically extended in approximately one-third of the cohort. Treatment improved locomotor function in these severely compromised animals after it had declined to the point at which animals normally die. This indicates that some pathology in LINCL is reversible and does not simply reflect neuronal death.

AB - Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal inherited neurodegenerative disease caused by loss of lysosomal protease tripeptidyl peptidase 1 (TPP1). We have investigated the effects of chronic intrathecal (IT) administration using enzyme replacement therapy (ERT) to the brain of an LINCL mouse model, in which locomotor function declines dramatically prior to early death. Median lifespan was significantly extended from 126 days to >259 days when chronic IT treatment was initiated before the onset of disease. While treated animals lived longer and showed little sign of locomotor dysfunction as measured by stride length, some or all (depending on regimen) still died prematurely. One explanation is that cerebrospinal fluid (CSF)-mediated delivery may not deliver TPP1 to all brain regions. Morphological studies support this, showing delivery of TPP1 to ventral, but not deeper and dorsal regions. When IT treatment is initiated in severely affected LINCL mice, lifespan was extended modestly in most but dramatically extended in approximately one-third of the cohort. Treatment improved locomotor function in these severely compromised animals after it had declined to the point at which animals normally die. This indicates that some pathology in LINCL is reversible and does not simply reflect neuronal death.

KW - chronic

KW - enzyme replacement therapy

KW - intrathecal

KW - neuronal ceroid lipofuscinosis

KW - tripeptidyl peptidase 1

UR - http://www.scopus.com/inward/record.url?scp=85015750770&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85015750770&partnerID=8YFLogxK

U2 - 10.1016/j.omtm.2017.01.004

DO - 10.1016/j.omtm.2017.01.004

M3 - Article

AN - SCOPUS:85015750770

VL - 4

SP - 204

EP - 212

JO - Molecular Therapy - Methods and Clinical Development

JF - Molecular Therapy - Methods and Clinical Development

SN - 2329-0501

ER -