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.

Keywords: Batten disease; CLN2; Dachshund; NCL; TPP1; cerebrospinal fluid; lysosomal storage disease; tripeptidyl peptidase-1.

Fig 1

Survival times of TPP1^–/– Dachshunds in the four treatment groups. Two of the dogs given the 16 mg dose were euthanized prior to reaching end-stage disease because they had developed meningitis or obstructive hydrocephalus. The dog receiving the 48 mg dose was euthanized before reaching end-stage disease because it had developed obstructive hydrocephalus. All remaining dogs were euthanized when they reached end-stage disease.

Fig 2

Ages of onset of neurological signs in TPP1^–/– dogs. For dogs treated with the 4 or 16 mg doses, bars indicate mean and SEM for the three dogs in each group. When no error bars are present, only one of the three dogs in the treatment group exhibited the indicated sign. Data from only one dog that received the 48 mg dose of rhTPP1 are shown. TL, thoracic limb; PL, pelvic limb; ND, sign did not appear prior to euthanasia.

Fig 3

T-maze performance of dogs in the different treatment groups. Data show the average number of incorrect choices. Vertical bars indicate SD when more than one dog was included in the data point. All groups started with three dogs, except one dog was included at the 48 mg-dose level. Among the TPP1^–/– dogs, some could not complete the T-maze test at the later time points, and testing of the wild-type dogs was suspended after 12–13 months. Among the TPP1^–/– dogs, in addition to the dog that received the 48 mg dose, data points representing fewer than three dogs are as follows: vehicle 9 months, n = 1; 4 mg 8–11 months, n = 2; 16 mg 13 months, n = 2; 14 months, n = 1. Error bars represent SD and are not shown for data points represented by only one animal.

Fig 4

Effect of rhTPP1 infusion on brain ventricular volume. There was a dose-related attenuation of ventricular enlargement in affected animals treated with rhTPP1 (n = 3/data point). Error bars represent SD. WT, wild type.

Fig 5

Representative three-dimensional images of brain ventricles reconstructed from MRI. The disease-related ventricular enlargement was inhibited by the TPP1 treatments.