title: Enzyme replacement therapy delays pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis.
abstract: 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.
authors: Department of Bioengineering, University of Missouri, Columbia, MO 65211, USA; Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211, USA.
authors: Rebecca E H
authors: RE
authors: Whiting
authors: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211, USA.
authors: Kristina
authors: K
authors: Narfström
authors: Department of Bioengineering, University of Missouri, Columbia, MO 65211, USA.
authors: Gang
authors: G
authors: Yao
authors: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211, USA.
authors: Jacqueline W
authors: JW
authors: Pearce
authors: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211, USA.
authors: Joan R
authors: JR
authors: Coates
authors: Department of Ophthalmology, University of Missouri, Columbia, MO 65212, USA.
authors: Leilani J
authors: LJ
authors: Castaner
authors: Department of Ophthalmology, University of Missouri, Columbia, MO 65212, USA.
authors: Cheryl A
authors: CA
authors: Jensen
authors: Department of Bioengineering, University of Missouri, Columbia, MO 65211, USA; Department of Ophthalmology, University of Missouri, Columbia, MO 65212, USA.
authors: Brittanie N
authors: BN
authors: Dougherty
authors: BioMarin Pharmaceutical Inc., Novato, CA 94949, USA.
authors: Brian R
authors: BR
authors: Vuillemenot
authors: BioMarin Pharmaceutical Inc., Novato, CA 94949, USA.
authors: Derek
authors: D
authors: Kennedy
authors: BioMarin Pharmaceutical Inc., Novato, CA 94949, USA.
authors: Charles A
authors: CA
authors: O'Neill
authors: Department of Bioengineering, University of Missouri, Columbia, MO 65211, USA; Department of Ophthalmology, University of Missouri, Columbia, MO 65212, USA. Electronic address: katzm@health.missouri.edu.
authors: Martin L
authors: ML
authors: Katz
mesh_terms: D000626:Aminopeptidases / Q000172:deficiency / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001369:Axons; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000172:deficiency / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D004596:Electroretinography / Q000187:drug effects; D056947:Enzyme Replacement Therapy; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000503:physiopathology; D009900:Optic Nerve / Q000166:cytology; D011994:Recombinant Proteins / Q000627:therapeutic use; D012025:Reflex, Pupillary / Q000187:drug effects*; D057057:Serine Proteases / Q000172:deficiency / Q000627:therapeutic use*; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D011994:Recombinant Proteins; D000091346:Tripeptidyl-Peptidase 1; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human
keywords: batten disease; brain; electroretinogram; ganglion cells; lysosomal storage disease; optic nerve; pupillary light reflex; retinal degeneration