Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease).
Bottom Line: 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.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.
Affiliation: Mason Eye Institute, University of Missouri School of Medicine, and Department of Bioengineering, University of Missouri, Columbia, Missouri.Show MeSH
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Mentions: Assessments of cognitive function were performed by using a T-maze test of spatial learning and memory (Sanders et al., 2011). After the initial training period in the T-maze, the dogs were evaluated monthly for performance of the reversal learning tasks, starting at 4 months of age. The mean number of errors made until reaching criterion at 4 months of age within each study group ranged from seven to nine (Fig. 3). Except for the vehicle-treated TPP1–/– dogs, the performance of the dogs improved progressively at subsequent monthly testing sessions. There were no significant differences in performance between the rhTPP1-treated affected dogs and the homozygous normal dogs at any of the time points. In contrast, the TPP1–/– dogs that received vehicle showed no improvement in T-maze performance. In fact, the performance of these dogs deteriorated sharply after 7 months of age. Two of the three dogs in this group were able to complete the T-maze testing only through 8 months of age. At 7–8 months of age, the performance of the TPP1–/– dogs that received both the 4 and 16 mg doses of rhTPP1 was significantly better that of the affected dogs that received vehicle (P < 0.05; Fig. 3). A dog that had received 48 mg doses of rhTPP1 was able to complete the task with fewer than two errors until 15 months of age and was able to continue performing this test until 18 months of age, with only a small decline in performance between 15 and 18 months (Fig. 3).
Affiliation: Mason Eye Institute, University of Missouri School of Medicine, and Department of Bioengineering, University of Missouri, Columbia, Missouri.