title: 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.affiliation: Mason Eye Institute, University of Missouri School of Medicine, and Department of Bioengineering, University of Missouri, Columbia, Missouri.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Katz
authors.forename: Joan R
authors.initials: JR
authors.lastname: Coates
authors.forename: Christine M
authors.initials: CM
authors.lastname: Sibigtroth
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Taylor
authors.forename: Melissa
authors.initials: M
authors.lastname: Carpentier
authors.forename: Whitney M
authors.initials: WM
authors.lastname: Young
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wininger
authors.forename: Derek
authors.initials: D
authors.lastname: Kennedy
authors.forename: Brian R
authors.initials: BR
authors.lastname: Vuillemenot
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Neill
mesh_terms: D000626:Aminopeptidases / Q000235:genetics / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology / Q000628:therapy; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D056947:Enzyme Replacement Therapy / Q000379:methods*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009460:Neurologic Examination; D009472:Neuronal Ceroid-Lipofuscinoses / Q000150:complications / Q000235:genetics / Q000628:therapy* / Q000662:veterinary*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D057057:Serine Proteases / Q000235:genetics / Q000627:therapeutic use*; D016019:Survival Analysis; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D011993:Recombinant Fusion Proteins; D000091346:Tripeptidyl-Peptidase 1; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human
keywords: Batten disease; CLN2; Dachshund; NCL; TPP1; cerebrospinal fluid; lysosomal storage disease; tripeptidyl peptidase-1