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.
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wiseman
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Nemtsova
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Matteson
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Neuroscience & Cell Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Millonig
authors.affiliation: School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Dirk F
authors.initials: DF
authors.lastname: Moore
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Biochemistry and Molecular Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Sleat
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Department of Biochemistry and Molecular Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Lobel
keywords: chronic; enzyme replacement therapy; intrathecal; neuronal ceroid lipofuscinosis; tripeptidyl peptidase 1