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

• 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
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2014.06.008

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.