C. Vogler et al., MURINE MUCOPOLYSACCHARIDOSIS TYPE-VII - THE IMPACT OF THERAPIES ON THE CLINICAL COURSE AND PATHOLOGY IN A MURINE MODEL OF LYSOSOMAL STORAGEDISEASE, Journal of inherited metabolic disease, 21(5), 1998, pp. 575-586
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.