title: Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis.
abstract: The CLN2 form of neuronal ceroid lipofuscinosis, a type of Batten disease, is a lysosomal storage disorder caused by a deficiency of the enzyme tripeptidyl peptidase-1 (TPP1). Patients exhibit progressive neurodegeneration and loss of motor, cognitive, and visual functions, leading to death by the early teenage years. TPP1-null Dachshunds recapitulate human CLN2 disease. To characterize the safety and pharmacology of recombinant human (rh) TPP1 administration to the cerebrospinal fluid (CSF) as a potential enzyme replacement therapy (ERT) for CLN2 disease, TPP1-null and wild-type (WT) Dachshunds were given repeated intracerebroventricular (ICV) infusions and the pharmacokinetic (PK) profile, central nervous system (CNS) distribution, and safety were evaluated. TPP1-null animals and WT controls received 4 or 16mg of rhTPP1 or artificial cerebrospinal fluid (aCSF) vehicle every other week. Elevated CSF TPP1 concentrations were observed for 2-3 days after the first ICV infusion and were approximately 1000-fold higher than plasma levels at the same time points. Anti-rhTPP1 antibodies were detected in CSF and plasma after repeat rhTPP1 administration, with titers generally higher in TPP1-null than in WT animals. Widespread brain distribution of rhTPP1 was observed after chronic administration. Expected histological changes were present due to the CNS delivery catheters and were similar in rhTPP1 and vehicle-treated animals, regardless of genotype. Neuropathological evaluation demonstrated the clearance of lysosomal storage, preservation of neuronal morphology, and reduction in brain inflammation with treatment. This study demonstrates the favorable safety and pharmacology profile of rhTPP1 ERT administered directly to the CNS and supports clinical evaluation in patients with CLN2 disease.
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA. Electronic address: bvuillemenot@bmrn.com.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Vuillemenot
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Kennedy
authors.affiliation: King's College London, London, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.affiliation: King's College London, London, UK.
authors.forename: Andrew M S
authors.initials: AM
authors.lastname: Wong
authors.affiliation: King's College London, London, UK.
authors.forename: Sarmi
authors.initials: S
authors.lastname: Sri
authors.affiliation: King's College London, London, UK.
authors.forename: Thom
authors.initials: T
authors.lastname: Doeleman
authors.affiliation: University of Missouri, Columbia, MO, USA.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Katz
authors.affiliation: University of Missouri, Columbia, MO, USA.
authors.forename: Joan R
authors.initials: JR
authors.lastname: Coates
authors.affiliation: University of Missouri, Columbia, MO, USA.
authors.forename: Gayle C
authors.initials: GC
authors.lastname: Johnson
authors.affiliation: Northern Biomedical Research, Muskegon, MI, USA.
authors.forename: Randall P
authors.initials: RP
authors.lastname: Reed
authors.affiliation: Northern Biomedical Research, Muskegon, MI, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Adams
authors.affiliation: Tox Path Specialists, Frederick, MD, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Butt
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Musson
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Henshaw
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Keve
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Rhea
authors.initials: R
authors.lastname: Cahayag
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Tsuruda
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Neill
mesh_terms: D000626:Aminopeptidases / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D000818:Animals; D000906:Antibodies / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000473:pathology / Q000648:ultrastructure; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D018450:Disease Progression; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D056947:Enzyme Replacement Therapy; D005838:Genotype; D057967:Infusions, Intraventricular; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D057057:Serine Proteases / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D000906:Antibodies; D011994:Recombinant Proteins; D000091346:Tripeptidyl-Peptidase 1; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human
keywords: Batten disease; CLN2; Intracerebroventricular; Intrathecal; Neuronal ceroid lipofuscinosis; Tripeptidyl peptidase-1