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

J Neurosci Res. 2014 Nov;92(11):1591-8. doi: 10.1002/jnr.23423. Epub 2014 Jun 17.


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.

Keywords: Batten disease; CLN2; Dachshund; NCL; TPP1; cerebrospinal fluid; lysosomal storage disease; tripeptidyl peptidase-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / genetics
  • Aminopeptidases / therapeutic use*
  • Analysis of Variance
  • Animals
  • Brain / pathology
  • Cognition Disorders / etiology
  • Cognition Disorders / therapy
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / 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
  • Maze Learning / physiology
  • Mutation / genetics
  • Neurologic Examination
  • Neuronal Ceroid-Lipofuscinoses / complications
  • Neuronal Ceroid-Lipofuscinoses / genetics
  • Neuronal Ceroid-Lipofuscinoses / therapy*
  • Neuronal Ceroid-Lipofuscinoses / veterinary*
  • Recombinant Fusion Proteins / administration & dosage
  • Serine Proteases / genetics
  • Serine Proteases / therapeutic use*
  • Survival Analysis


  • Recombinant Fusion Proteins
  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • tripeptidyl-peptidase 1