Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease).

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.

• Authors: Martin L Katz, Joan R Coates, Christine M Sibigtroth, Jacob D Taylor, Melissa Carpentier, Whitney M Young, Fred A Wininger, Derek Kennedy, Brian R Vuillemenot, Charles A O'Neill
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 92 Issue 11 Pg. 1591-8 (Nov 2014) ISSN: 1097-4547 [Electronic] United States
• PMID: 24938720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

Chemical References

• Recombinant Fusion Proteins
• Tripeptidyl-Peptidase 1
• Serine Proteases
• Aminopeptidases
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• TPP1 protein, human

Topics

• Aminopeptidases (genetics, therapeutic use)
• Analysis of Variance
• Animals
• Brain (pathology)
• Cognition Disorders (etiology, therapy)
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (genetics, therapeutic use)
• Disease Models, Animal
• Disease Progression
• Dogs
• Enzyme Replacement Therapy (methods)
• Female
• Humans
• Image Processing, Computer-Assisted
• Magnetic Resonance Imaging
• Male
• Maze Learning (drug effects, physiology)
• Mutation (genetics)
• Neurologic Examination
• Neuronal Ceroid-Lipofuscinoses (complications, genetics, therapy, veterinary)
• Recombinant Fusion Proteins (administration & dosage)
• Serine Proteases (genetics, therapeutic use)
• Survival Analysis
• Tripeptidyl-Peptidase 1