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: Progressive brain atrophy that characterizes CLN2 disease was measured by assessing the increase in brain ventricle volume as estimated by MRI. Brain ventricular volumes were determined in the dogs at approximately 2, 6.5, and 11 months of age (Figs. 4, 5). Among the TPP1+/+ dogs, there were only modest increases in ventricular volumes over this age range as the dogs matured (mean increase in ventricular volume for all of the TPP1+/+ dogs was 946 mm3). Among the TPP1–/– dogs that received vehicle, mean ventricular volume increased by almost 7,500 mm3 over this age range (P < 0.01 relative to the TPP1+/+ dogs). CSF infusion of rhTPP1 significantly reduced the disease-related ventricular enlargement. Relative to vehicle-treated TPP1–/– dogs, the group that included all affected dogs treated with rhTPP1 exhibited a significant reduction in age-related ventricular enlargement (P < 0.01; Figs. 4, 5). There was a trend of greater inhibition of ventricular enlargement with higher doses of rhTPP1 (Fig. 4), but the samples were not large enough to determine whether this dose-level effect was significant. For all of the rhTPP1-treated TPP1–/– dogs combined, ventricular volume increased by a mean of 4,864 mm3 between 2 and 11 months of age (P < 0.05 compared with the vehicle-treated TPP1–/– dogs). Representative three-dimensional reconstructions of the ventricles of vehicle-treated TPP1+/+, vehicle-treated TPP1–/–, and 48 mg-rhTPP1-treated TPP1–/– dogs are shown in Figure 5.
Affiliation: Mason Eye Institute, University of Missouri School of Medicine, and Department of Bioengineering, University of Missouri, Columbia, Missouri.