title: Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression.
abstract: CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of life span. We hypothesized that the treatment may not deliver therapeutic levels of this protein to tissues outside the central nervous system that also require TPP1 for normal lysosomal function. To test this hypothesis, dogs treated with CSF administration of AAV-TPP1 were evaluated for the development of non-neuronal pathology. Affected treated dogs exhibited progressive cardiac pathology reflected by elevated plasma cardiac troponin-1, impaired cardiac function and development of histopathological myocardial lesions. Progressive increases in the plasma activity levels of alanine aminotransferase and creatine kinase indicated development of pathology in the liver and muscles. The treatment also did not prevent disease-related accumulation of lysosomal storage bodies in the heart or liver. These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system.
authors.affiliation: Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, MO, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Katz
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO USA.
authors.forename: G C
authors.initials: GC
authors.lastname: Johnson
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Leach
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
authors.forename: B G
authors.initials: BG
authors.lastname: Williamson
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Coates
authors.affiliation: Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, MO, USA.
authors.forename: R E H
authors.initials: REH
authors.lastname: Whiting
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Vansteenkiste
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Whitney
mesh_terms: D000626:Aminopeptidases / Q000235:genetics* / Q000627:therapeutic use; D000818:Animals; D000229:Dependovirus; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004285:Dogs; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D057967:Infusions, Intraventricular; D016464:Lysosomal Storage Diseases / Q000235:genetics / Q000628:therapy*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000628:therapy*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D057057:Serine Proteases / Q000235:genetics* / Q000627:therapeutic use; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D000091346:Tripeptidyl-Peptidase 1; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human