Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis

Mol Ther. 2008 Apr;16(4):649-56. doi: 10.1038/mt.2008.9. Epub 2008 Feb 12.


Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive neurodegenerative disease caused by mutations in CLN2, which encodes the lysosomal protease tripeptidyl peptidase 1 (TPP1). LINCL is characterized clinically by progressive motor and cognitive decline, and premature death. Enzyme-replacement therapy (ERT) is currently available for lysosomal storage diseases affecting peripheral tissues, but has not been used in patients with central nervous system (CNS) involvement. Enzyme delivery through the cerebrospinal fluid is a potential alternative route to the CNS, but has not been studied for LINCL. In this study, we identified relevant neuropathological and behavioral hallmarks of disease in a mouse model of LINCL and correlated those findings with tissues from LINCL patients. Subsequently, we tested if intraventricular delivery of TPP1 to the LINCL mouse was efficacious. We found that infusion of recombinant human TPP1 through an intraventricular cannula led to enzyme distribution in several regions of the brain of treated mice. In vitro activity assays confirm increased TPP1 activity throughout the rostral-caudal extent of the brain. Importantly, treated mice showed attenuated neuropathology, and decreased resting tremor relative to vehicle-treated mice. This data demonstrates that intraventricular enzyme delivery to the CNS is feasible and may be of therapeutic value.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aminopeptidases
  • Animals
  • Astrocytes / metabolism
  • Brain / enzymology
  • Brain / pathology
  • Cerebral Ventricles
  • Child
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • Disease Models, Animal
  • Endopeptidases / genetics
  • Endopeptidases / metabolism
  • Endopeptidases / therapeutic use*
  • Glial Fibrillary Acidic Protein / metabolism
  • Humans
  • Infant
  • Mice
  • Mice, Knockout
  • Neuronal Ceroid-Lipofuscinoses / pathology
  • Neuronal Ceroid-Lipofuscinoses / physiopathology
  • Neuronal Ceroid-Lipofuscinoses / therapy*
  • Neurons / metabolism
  • Phenotype
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology
  • Recombinant Proteins / therapeutic use
  • Serine Proteases


  • Glial Fibrillary Acidic Protein
  • Recombinant Proteins
  • Endopeptidases
  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • tripeptidyl-peptidase 1