Enzyme replacement therapy delays pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis

Late-infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a hereditary neurological disorder characterized by progressive retinal degeneration and vision loss, cognitive and motor decline, seizures, and pronounced brain atrophy. This fatal pediatric disease is caused by mutations in the CLN2 g...

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Bibliographic Details
Published in:Experimental eye research 2014-08, Vol.125, p.164-172
Main Authors: Whiting, Rebecca E.H., Narfström, Kristina, Yao, Gang, Pearce, Jacqueline W., Coates, Joan R., Castaner, Leilani J., Jensen, Cheryl A., Dougherty, Brittanie N., Vuillemenot, Brian R., Kennedy, Derek, O'Neill, Charles A., Katz, Martin L.
Format: Article
Language:English
Subjects:
Aminopeptidases - deficiency
Aminopeptidases - therapeutic use
Analysis of Variance
Animals
Axons
batten disease
brain
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - deficiency
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - therapeutic use
Disease Models, Animal
Disease Progression
Dogs
electroretinogram
Electroretinography - drug effects
Enzyme Replacement Therapy
ganglion cells
lysosomal storage disease
Neuronal Ceroid-Lipofuscinoses - drug therapy
Neuronal Ceroid-Lipofuscinoses - physiopathology
optic nerve
Optic Nerve - cytology
pupillary light reflex
Recombinant Proteins - therapeutic use
Reflex, Pupillary - drug effects
retinal degeneration
Serine Proteases - deficiency
Serine Proteases - therapeutic use
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Summary:Late-infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a hereditary neurological disorder characterized by progressive retinal degeneration and vision loss, cognitive and motor decline, seizures, and pronounced brain atrophy. This fatal pediatric disease is caused by mutations in the CLN2 gene which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Utilizing a TPP1−/− Dachshund model of CLN2 disease, studies were conducted to assess the effects of TPP1 enzyme replacement administered directly to the CNS on disease progression. Recombinant human TPP1 (rhTPP1) or artificial cerebrospinal fluid vehicle was administered to CLN2-affected dogs via infusion into the CSF. Untreated and vehicle treated affected dogs exhibited progressive declines in pupillary light reflexes (PLRs) and electroretinographic (ERG) responses to light stimuli. Studies were undertaken to determine whether CSF administration of rhTPP1 alters progression of the PLR and ERG deficits in the canine model. rhTPP1 administration did not inhibit the decline in ERG responses, as rhTPP1 treated, vehicle treated, and untreated dogs all exhibited similar progressive and profound declines in ERG amplitudes. However, in some of the dogs treated with rhTPP1 there were substantial delays in the appearance and progression of PLR deficits compared with untreated or vehicle treated affected dogs. These findings indicate that CSF administration of TPP1 can attenuate functional impairment of neural pathways involved in mediating the PLR but does not prevent loss of retinal responses detectable with ERG. •Enzyme replacement therapy (ERT) to the CSF was evaluated for treating NCL in dogs.•ERT preserved the pupillary light reflex but not the electroretinogram.•ERT to the CSF will need to be supplemented with treatments targeted to the eye.
ISSN:0014-4835
1096-0007
DOI:10.1016/j.exer.2014.06.008