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Enzyme replacement therapy attenuates disease progression in a canine model of late‐infantile neuronal ceroid lipofuscinosis ( <scp>CLN</scp> 2 disease)
- Source :
- Journal of Neuroscience Research
- Publication Year :
- 2014
- Publisher :
- Wiley, 2014.
-
Abstract
- Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5–11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated.
- Subjects :
- Male
Batten disease
Pathology
medicine.medical_specialty
Recombinant Fusion Proteins
Disease
Biology
Aminopeptidases
cerebrospinal fluid
Cellular and Molecular Neuroscience
Dogs
Atrophy
Cerebrospinal fluid
Neuronal Ceroid-Lipofuscinoses
Image Processing, Computer-Assisted
medicine
Lysosomal storage disease
Animals
Humans
Enzyme Replacement Therapy
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
Maze Learning
Hereditary Neurodegenerative Disorder
Research Articles
TPP1
Neurologic Examination
Analysis of Variance
Tripeptidyl-Peptidase 1
CLN2
Brain
NCL
Enzyme replacement therapy
medicine.disease
Magnetic Resonance Imaging
Survival Analysis
Disease Models, Animal
Dachshund
lysosomal storage disease
Mutation
Disease Progression
Female
Neuronal ceroid lipofuscinosis
Serine Proteases
Cognition Disorders
tripeptidyl peptidase-1
Subjects
Details
- ISSN :
- 10974547 and 03604012
- Volume :
- 92
- Database :
- OpenAIRE
- Journal :
- Journal of Neuroscience Research
- Accession number :
- edsair.doi.dedup.....ee8180863fecaf8eb166a6defb4b1ba5