Long-term normalization in the central nervous system, ocular manifestations, and skeletal deformities by a single systemic adenovirus injection into neonatal mice with mucopolysaccharidosis VII

Abstract

Systemic injection of an adenovirus vector into adult mice resulted in pathological improvements in multiple visceral organs of mice with mucopolysaccharidosis VII; however, no therapeutic efficacy was observed for mental retardation, skeletal deformities, corneal clouding, and retinal degeneration. In this study, an adenovirus vector expressing human bglucuronidase was injected into mice with mucopolysaccharidosis VII within 24 h of birth, and therapeutic efficacy was evaluated. In the brains of the mice, more than 20% of GUSB activity was maintained for at least 20 weeks after birth, and histopathological analysis showed no obvious lysosomal storage. Furthermore, no vacuolated cells were detected in corneal stroma and retinal pigment epithelium in the eyes of the mice treated in the neonatal period, while pathological improvement was not observed in adult MPSVII mice that received similar treatments. The treated mice also lacked characteristic facial skeletal deformities, and radiographic analysis demonstrated that their facial and cranial bones were morphologically normal. These results indicate that a single systemic adenovirus injection in the neonatal period could prevent the progression of mental retardation, corneal clouding, retinal degeneration, and skeletal deformities, all of which are frequently observed clinical manifestations and difficult to treat in adulthood.

Encapsulation Cell Therapy for Mucopolysaccharidosis Type VII Using Genetically Engineered Immortalized Human Amniotic Epithelial Cells

“…Human β -glucuronidase (GUSB) is heat-stable, and was reduced by only 30% after 2-hrs incubation at 65°C. In contrast, the GUSB of C3H mice is heat-labile, and its activity is almost completely eliminated by the same treatment (Kamata et al 2003). There was significant difference between the control group and AxCAhGUS-transduced IHAE cells group in the GUSB concentration of the implanted side brain tissue (Fig.…”

“…Enzyme replacement therapy corrected visceral pathology but showed little change in the lysosomal distensions in brain of adult MPSVII mice, because infused GUSB could not cross the blood-brain barrier (BBB) in mice after 14th day of age (Vogler et al 1999). In virus-or cell-mediated gene therapy, GUSB-encoding viral vectors or genetically modified cells were transplanted into MPSVII mice, but neither improved the CNS abnormalities of adult MPSVII mice (Wolfe et al 1992;Marechal et al 1993;Moullier et al 1993a, b;Ross et al 2000;Kamata et al 2003). Because the therapeutic agents including bone marrow, enzyme, viral vectors, genetically modified cells cannot cross the BBB, therapeutic effects for CNS lesions was limited in the neonatal period.…”

Fetal and neonatal gene therapy: benefits and pitfalls

“…Lysosomal storage diseases such as the mucopolysaccaridoses, including Sly, Hunter and Hurler syndromes, Tay-Sachs disease and globoid cell leukodystrophy, demonstrate fetal pathology (discussed in Casal and Wolfe 18 ); nevertheless, substantial therapeutic benefits have been observed in mouse and dog models following neonatal gene therapy. 3,4,6 Both in humans with Duchenne muscular dystrophy and in the diaphragm of the mdx mouse model, repeated straining of the muscle causes myofibre damage and degeneration ( Figure 1c). Eventually, muscular atrophy ensues as regeneration fails to compensate for ongoing necrosis.…”

“…These include glycogen storage disease type Ia, 1 mucopolysaccharidosis type VII, [2][3][4][5][6] bilirubin-UDP-glucuronosyltransferase deficiency (Crigler-Najjar syndrome), 7,8 haemophilias A 9 and B [10][11][12] and congenital blindness (Leber congenital amaurosis). 13 To fully understand the basis of these successful experiments in order to move towards clinical application, several key factors concerning early gene transfer must be closely examined.…”

Gene Therapy Approaches for Lysosomal Storage Disease: Next-Generation Treatment

“…Widespread correction of tissues including liver, kidney, and skeletal muscle in animal models of LSDs including MPS VII, Fabry disease, and Pompe disease has been reported. Hurdles for this strategy include long-term persistent expression of the therapeutic transgene, interaction with the host immune system, and lack of correction of isolated tissues such as brain, eye, and bone (Kosuga et al, 2000;Ziegler et al, 2002;Kamata et al, 2003;Kiang et al, 2006). AdV studies have focused more on delivery of vector directly to affected tissues, in particular the brain; however, most studies resulted in limited expression duration (Stein et al, 1999;Hsich et al, 2002;Eto et al, 2004).…”