Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by beta-glucuronidase (GUSB) deficiency. This disease exhibits a broad spectrum of clinical signs including skeletal dysplasia, retinal degeneration, cognitive deficits and hearing impairment. Sustained, high-level expression of GUSB significantly improves the clinical course of the disease in the murine model of MPS VII. Low levels of enzyme expression (1-5% of normal) can significantly reduce the biochemical and histopathological manifestations of MPS VII. However, it has not been clear from previous studies whether persistent, low levels of circulating GUSB lead to significant improvements in the clinical presentation of this disease. We generated a rAAV2 vector that mediates persistent, low-level GUSB expression in the liver. Liver and serum levels of GUSB were maintained at approximately 5% and approximately 2.5% of normal, respectively, while other tissue ranged from background levels to 0.9%. This level of activity significantly reduced the secondary elevations of alpha-galactosidase and the levels of glycosaminoglycans in multiple tissues. Interestingly, this level of GUSB was also sufficient to reduce lysosomal storage in neurons in the brain. Although there were small but statistically significant improvements in retinal function, auditory function, skeletal dysplasia, and reproduction in rAAV-treated MPS VII mice, the clinical deficits were still profound and there was no improvement in lifespan. These data suggest that circulating levels of GUSB greater than 2.5% will be required to achieve substantial clinical improvements in MPS VII.
Cardiovascular manifestations of lysosomal storage disease (LSD) are a significant health problem for affected patients. Infantileonset cardiac disease, because of its rapid progression, is usually treated symptomatically. Therapy in older patients includes valve replacement and bone marrow (BM) transplantation, both of which are life threatening in the already debilitated patients. Enzyme replacement therapy has potential benefit but has not yet been demonstrated to provide long-term relief for cardiac disease. Here, we demonstrate prevention of severe cardiac manifestations in -glucuronidase (GUSB) null mice BM-transplanted i.v. as neonates without myeloablative pretreatment. The mice, a model of mucopolysaccharidosis type VII (MPSVII, Sly syndrome), develop progressive LSD unless provided with GUSB early in life. The BM recipients retained GUSB؉ donor cells in the peripheral blood and heart until necropsy at >11 months of age. The enzyme -hexosamindase increased in tissues of GUSB null MPSVII mice was reduced significantly (P ؍ 0.001) in treated MPSVII hearts. Electrocardiography demonstrated normalization of heart rate, PR, PQ, and QRS intervals in BM recipients. Storage was markedly reduced in the stroma of heart valves, adventitial cells of the aortic root, perivascular and interstitial cells of the myocardium, and interstitial cells of the conduction tissue. Heart͞body weight ratio normalized. The aortic root was still grossly distended, and the conductive myocytes retained storage, suggesting neither plays a major role in ECG normalization. We conclude that transplantation of MPSVII neonates without toxic intervention can prevent many of the cardiovascular manifestations of LSD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.