MURINE MUCOPOLYSACCHARIDOSIS TYPE-VII - THE IMPACT OF THERAPIES ON THE CLINICAL COURSE AND PATHOLOGY IN A MURINE MODEL OF LYSOSOMAL STORAGEDISEASE

Murine mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a recessively inherited deficiency of the lysosomal enzyme beta-glucuronidase. Affected mice have clinical, biochemical a nd pathological findings similar to those seen in humans with MPS Vn ( Sly syndrome), including growth retardation, facial dysmorphism, deafn ess, behavioural deficits and widespread glycosaminoglycan storage in lysosomes in the viscera, skeleton and brain. This mouse model is a us eful tool for the evaluation of the effectiveness and experimental the rapies for the MPS disorders. Syngeneic bone marrow transplantation pe rformed in newborn MPS VII animals-before clinical evidence of disease is pronounced-prolongs life, improves hearing and bone growth, and pr events lysosomal storage in many sites, but does not correct the centr al nervous system disease. Enzyme therapy with beta-glucuronidase from the first days of life does reduce lysosomal storage in the brain in murine MPS VII. The enzyme-replaced mice also have reduced visceral ly sosomal storage, impressive normalization of their phenotype and an im proved life span. The effectiveness of gene therapy for the treatment of lysosomal storage disease has also been tested using the MPS VII mo del. When transplanted into MPS VII mice, syngeneic haematopoietic ste m cells or mouse skin fibroblasts infected with retrovirus expressing beta-glucuronidase decreased storage, but only in the liver and spleen . Injection of an adenovirus vector expressing beta-glucuronidase into the vitreous of the MPS VII mice reduced storage in the retinal pigme nt epithelium and corneal endothelium. Intravenous administration of t he adenovirus vector transduced with the beta-glucuronidase gene reduc ed liver and spleen storage and, when instilled into the cerebral vent ricles, this viral vector caused beta-glucuronidase production in epit helial cells lining the ventricles. Recently, retroviral vector-correc ted MPS VII fibroblasts secreting high levels of beta-glucuronidase we re engrafted directly into the brains of adult MPS VII mice with resul tant reduction in storage in neurons and glia adjacent to the grafts. Future efforts aimed at prolonging expression of the beta-glucuronidas e gene by viral vectors and more precisely directing the therapeutic e ffect to the skeleton and brain will be important in optimizing treatm ents for murine MPS VII and extending the results of such therapies to humans with MPS.