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Rebecca Whiting, Kristina Narfström, Gang Yao, Jacqueline W. Pearce, Leilani Castaner, Brian Vuillemenot, Derek Kennedy, Martin L. Katz; Enzyme Replacement Attenuates Pupillary Light Reflex Deficits in a Canine Model of Late Infantile Neuronal Ceroid Lipofuscinosis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2448.
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Pupillary light reflex (PLR) alterations are valuable indicators of neurodegenerative disease affecting the visual and/or central nervous systems. Dachshunds with hereditary late infantile neuronal ceroid lipofuscinosis (LINCL) lack the lysosomal enzyme tripeptidyl-peptidase-1 (TPP1) and develop progressive neurologic signs similar to those seen in human LINCL including cognitive and motor impairment, vision loss, seizures, and premature death. The current objective is to quantify PLR changes in the Dachshund model as a basis for evaluating the efficacy of enzyme replacement in the central nervous system.
The study included LINCL-affected dogs (n=11) and related normal Dachshunds (n=9). Six affected and five normal dogs received TPP1 replacement enzyme administered via the cerebrospinal fluid (BioMarin Pharmaceutical Inc.), while the others did not. Using a custom-built system, the PLR was recorded in each dog at 6, 8, and/or 10 months of age. Dogs were dark-adapted, placed under general anesthesia, and subjected to a series of 100 millisecond, white light flashes of increasing intensity (0.1 to 1400 lux). Recorded images were analyzed for pupil area, and percent pupil constriction was determined for each stimulus. Electroretinography (ERG) was performed in sedated dogs using a portable, full-field flash system and standardized protocol. A- and b-wave amplitudes were evaluated in order to objectively assess retinal function.
Affected dogs treated with TPP1 enzyme replacement retained normal pupil constriction amplitude with all light intensities tested. Conversely, affected dogs that did not receive TPP1 replacement enzyme exhibited reduced PLR constriction amplitude compared to normal dogs for all intensities except the brightest (p<0.05). All affected dogs had severely impaired inner retinal function by 6 months of age as demonstrated by reduced ERG b-wave amplitudes.
These results indicate that administration of TPP1 enzyme to the central nervous system attenuates LINCL-related deficits in PLR constriction in this canine model. This effect is likely due to preservation of central neural elements of the PLR pathway since retinal function was not preserved in enzyme-treated dogs.
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