Improvement of skeletal lesions in mice with mucopolysaccharidosis type VII by neonatal adenoviral gene transfer.
Neonatal gene transfer using adenovirus vectors expressing human beta-glucuronidase (AxCAhGUS) resulted in pathological improvement in multiple visceral organs of mice with mucopolysaccharidosis type VII (MPSVII). However, the therapeutic effect on skeletal deformities and growth retardation, the major clinical symptoms in MPSVII, was not fully investigated by biochemical and histopathological analyses. In this study, we injected AxCAhGUS into a murine model of MPSVII (B6/MPSVII) within 24 h of birth and evaluated the therapeutic effects on skeletal deformities and growth retardation. High levels of beta-glucuronidase (GUSB) activity (approximately threefold higher than normal GUSB activity) were observed in the articular cartilage of the mice 30 days after the treatment. Histopathological study in the knee joints showed elimination of vacuole cells in the articular cartilage and growth plate. Subchondral bone near the articular surface was almost normal in the treated MPSVII mice. Long-term observation (for 140 days after treatment) indicated that characteristic phenotypes such as flattened face, hunched stature, and shortening of bone length in the treated mice were almost normal. These results demonstrate that a single injection of adenovirus vector into neonatal MPSVII mice is sufficient for long-term normalization of skeletal deformities and effective in pathological correction of the articular cartilage and growth plate.
National Research Institute of Child Health and Development, 157-8535, Tokyo, Japan.
Arihiko
A
Kanaji
Motomichi
M
Kosuga
Xiao Kang
XK
Li
Yasuyuki
Y
Fukuhara
Akiko
A
Tanabe
Yuko
Y
Kamata
Noriyuki
N
Azuma
Masao
M
Yamada
Toyonori
T
Sakamaki
Yoshiaki
Y
Toyama
Torayuki
T
Okuyama
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D001847:Bone Diseases / Q000473:pathology / Q000628:therapy; D002356:Cartilage / Q000378:metabolism; D002460:Cell Line; D019902:Chondrocytes / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D004195:Disease Models, Animal; D004705:Endocytosis; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D016538:Mucopolysaccharidosis VII / Q000628:therapy*; D010641:Phenotype; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D013997:Time Factors
D004279:DNA, Viral; D017527:Receptor, IGF Type 2; D005966:Glucuronidase