Enzyme replacement therapy (ERT) procedure for mucopolysaccharidosis type II (MPS II) by intraventricular administration (IVA) in murine MPS II.
Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and is characterized by the accumulation of glycosaminoglycans (GAGs). MPS II has been treated by hematopoietic stem cell therapy (HSCT)/enzyme replacement therapy (ERT), but its effectiveness in the central nervous system (CNS) is limited because of poor enzyme uptake across the blood-brain barrier (BBB). To increase the efficacy of ERT in the brain, we tested an intraventricular ERT procedure consisting of repeated administrations of IDS (20 μg/mouse/3 weeks) in IDS-knockout, MPS II model mice. The IDS enzyme activity and the accumulation of total GAGs were measured in mouse brains. The IDS activity was significantly increased, and the accumulation of total GAGs was decreased in the MPS II mouse brains treated with multiple administrations of IDS via intraventricular ERT. Additionally, a high level of IDS enzyme activity was appreciated in other MPS II mouse tissues, such as the liver, spleen, testis and others. A Y-maze was used to test learning and memory after repeated intraventricular ERT with IDS. The IDS-treated mouse groups recovered the capacity for short-term memory and activity. Although large and small vacuoles were found at the margin of the cerebellar Purkinje cells in the disease-control mice, these vacuoles disappeared upon treated with IDS. Loss of vacuoles was also observed in other tissues (liver, kidney and testis). These results demonstrate the possible efficacy of an ERT procedure with intraventricular administration of IDS for the treatment of MPS II.
Department of Genetic Diseases & Genomic Science, The Jikei University School of Medicine, Tokyo, Japan.
Takashi
T
Higuchi
Hiromi
H
Shimizu
Takahiro
T
Fukuda
Shiho
S
Kawagoe
Juri
J
Matsumoto
Yohta
Y
Shimada
Hiroshi
H
Kobayashi
Hiroyuki
H
Ida
Toya
T
Ohashi
Hideto
H
Morimoto
Tohru
T
Hirato
Katsuya
K
Nishino
Yoshikatsu
Y
Eto
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D007066:Iduronate Sulfatase / Q000008:administration & dosage / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D016532:Mucopolysaccharidosis II / Q000175:diagnosis / Q000628:therapy*; D010641:Phenotype; D013737:Testis / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
D007066:Iduronate Sulfatase