corneal alterations during combined therapy with cyclodextrinallopregnanolone and miglustat in a knock-out mouse model of npc1 disease在联合治疗角膜改变cyclodextrinallopregnanolone和miglustat淘汰赛npc1疾病的小鼠模型.pdf
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Corneal Alterations during Combined Therapy with
Cyclodextrin/Allopregnanolone and Miglustat in a
Knock-Out Mouse Model of NPC1 Disease
1,2 2 2 1 2 3
Marine Hovakimyan *, Jana Petersen , Fabian Maass , Maria Reichard , Martin Witt , Jan Lukas ,
1 1 3 2
Oliver Stachs , Rudolf Guthoff , Arndt Rolfs , Andreas Wree
1 Department of Ophthalmology, University of Rostock, Rostock, Germany, 2 Department of Anatomy, University of Rostock, Rostock, Germany, 3 Albrecht-Kossel-Institute
for Neuroregeneration, University of Rostock, Rostock, Germany
Abstract
Background: Niemann Pick disease type C1 is a neurodegenerative disease caused by mutations in the NPC1 gene, which
result in accumulation of unesterified cholesterol and glycosphingolipids in the endosomal-lysosomal system as well as
limiting membranes. We have previously shown the corneal involvement in NPC1 pathology in form of intracellular
inclusions in epithelial cells and keratocytes. The purpose of the present study was to clarify if these inclusions regress
during combined substrate reduction- and by-product therapy (SRT and BPT).
Methodology/Principal Findings: Starting at postnatal day 7 (P7) and thereafter, NPC1 knock-out mice (NPC12/ 2) and wild
type controls (NPC1+/+) were injected with cyclodextrin/allopregnanolone weekly. Additionally, a daily miglustat injection
started at P10 until P23. Starting at P23 the mice were fed powdered chow with daily addition of miglustat. The sham group
was injected with 0.9% NaCl at P7, thereafter daily starting at P10 until P23, and fed powdered chow starting at P23. For
corneal examination, in vivo confocal laser
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