title: Intrathecal tripeptidyl-peptidase 1 reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis.
abstract: Late infantile neuronal ceroid lipofuscinosis (LINCL) is caused by mutations in the gene encoding tripeptidyl-peptidase 1 (TPP1). LINCL patients accumulate lysosomal storage materials in the CNS accompanied by neurodegeneration, blindness, and functional decline. Dachshunds homozygous for a null mutation in the TPP1 gene recapitulate many symptoms of the human disease. The objectives of this study were to determine whether intrathecal (IT) TPP1 treatment attenuates storage accumulation and functional decline in TPP1-/- Dachshunds and to characterize the CNS distribution of TPP1 activity. TPP1 was administered to one TPP1-/- and one homozygous wild-type (WT) dog. An additional TPP1-/- and WT dog received vehicle. Four IT administrations of 32 mg TPP1 formulated in 2.3 mL of artificial cerebrospinal fluid (aCSF) or vehicle were administered monthly via the cerebellomedullary cistern from four to seven months of age. Functional decline was assessed by physical and neurological examinations, electrophysiology, and T-maze performance. Neural tissues were collected 48 h after the fourth administration and analyzed for TPP1 activity and autofluorescent storage material. TPP1 was distributed at greater than WT levels in many areas of the CNS of the TPP1-/- dog administered TPP1. The amount of autofluorescent storage was decreased in this dog relative to the vehicle-treated affected control. No improvement in overall function was observed in this dog compared to the vehicle-treated TPP1-/- littermate control. These results demonstrate for the first time in a large animal model of LINCL widespread delivery of biochemically active TPP1 to the brain after IT administration along with a decrease in lysosomal storage material. Further studies with this model will be necessary to optimize the dosing route and regimen to attenuate functional decline.
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA 94949, USA. bvuillemenot@bmrn.com
authors.forename: Brian R
authors.initials: BR
authors.lastname: Vuillemenot
authors.forename: Martin L
authors.initials: ML
authors.lastname: Katz
authors.forename: Joan R
authors.initials: JR
authors.lastname: Coates
authors.forename: Derek
authors.initials: D
authors.lastname: Kennedy
authors.forename: Pascale
authors.initials: P
authors.lastname: Tiger
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kanazono
authors.forename: Peter
authors.initials: P
authors.lastname: Lobel
authors.forename: Istvan
authors.initials: I
authors.lastname: Sohar
authors.forename: Su
authors.initials: S
authors.lastname: Xu
authors.forename: Rhea
authors.initials: R
authors.lastname: Cahayag
authors.forename: Steve
authors.initials: S
authors.lastname: Keve
authors.forename: Eugen
authors.initials: E
authors.lastname: Koren
authors.forename: Stuart
authors.initials: S
authors.lastname: Bunting
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Tsuruda
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Neill
mesh_terms: D000626:Aminopeptidases / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016466:CHO Cells; D002490:Central Nervous System / Q000378:metabolism; D002850:Chromatography, Gel; D002852:Chromatography, Ion Exchange; D006224:Cricetinae; D003412:Cricetulus; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004594:Electrophysiology; D005453:Fluorescence; D055786:Gene Knockout Techniques; D006801:Humans; D007118:Immunoassay; D007073:Immunoglobulin E / Q000097:blood; D007278:Injections, Spinal; D008247:Lysosomes / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D018782:Maze Learning / Q000187:drug effects; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D057057:Serine Proteases / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D011994:Recombinant Proteins; D000091346:Tripeptidyl-Peptidase 1; D007073:Immunoglobulin E; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human