Murine mucopolysaccharidosis type VII: long term therapeutic effects of enzyme replacement and enzyme replacement followed by bone marrow transplantation.

Abstract

We demonstrated previously that short term administration of recombinant ␤ -glucuronidase to newborn mice with mucopolysaccharidosis type VII reduced lysosomal storage in many tissues. Lysosomal storage accumulated gradually after cessation of enzyme replacement therapy. Mice alive at 1 yr of age had decreased bone deformities and less lysosomal storage in cortical neurons. Here we compare the effects of long term enzyme replacement initiated either at birth or at 6 wk of age, and of enzyme administration initiated at birth followed by syngeneic bone marrow transplantation (BMT) at 5 wk of age. Several mice from each treatment group lived to at least 1 yr of age. Liver and spleen samples had ␤ -glucuronidase levels ranging from 2.4 to 19.8% of normal and showed a parallel decrease in lysosomal storage. The combination of enzyme replacement therapy followed by BMT reduced lysosomal distension in meninges, corneal fibroblasts, and bone when compared with treatment with enzyme alone. Mice treated at birth had less lysosomal storage in some neurons of the brain and the skeletal dysplasia was less severe when compared to mice whose treatment was delayed until 6 wk of age. We conclude that both enzyme replacement alone and early enzyme replacement followed by BMT have long term positive effects on murine mucopolysaccharidosis type VII. In addition, treatment started at birth is far more effective than treatment initiated in young adults. ( J. Clin. Invest. 1997. 1596-1605.)

Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer

“…Based on previous studies using ERT and BMT, it seems likely that the primary mechanism for improvements in weight, bone length, and dysmorphic features seen in this study are the high levels of GUSB produced during the first month of life. 12,13 As shown previously, animals that received ERT for only the first 5 weeks of life showed essentially the same improvements in bone length and phenotype as animals who received long-term ERT. 11 Persistence of GUSB activity, however, may be more important in organs where progressive dysfunction can continue throughout life, or in tissues where storage material rapidly reaccumulates after therapy is stopped, such as the eye.…”

“…A number of studies have examined the benefits of neonatal versus adult treat-ments in the MPS VII mouse, using BMT, ERT, or a combination of the two. [10][11][12][13] These experiments have demonstrated that many of the functional deficits are amenable to therapy early in life, and that irreversible developmental damage does not occur in utero. It has been shown that reversal of lysosomal storage can be accomplished in most organs by either neonatal or adult treatments, although the duration of the histopathologic correction varies depending on the tissue and treatment method.…”

“…6,9,11,12 A notable exception to this statement is the brain, where the blood-brain barrier blocks ERTmediated correction in adult life. 9,13,14 Improvements in survival and retinal function can also be achieved by treatment in either the adult or neonatal period. 6,13,15 However, improvements in bone length, auditory function, or higher mental functions have only been documented following neonatal BMT or ERT.…”

“…9,13,14 Improvements in survival and retinal function can also be achieved by treatment in either the adult or neonatal period. 6,13,15 However, improvements in bone length, auditory function, or higher mental functions have only been documented following neonatal BMT or ERT. 9,10,12,16 Despite the successes seen in this mouse model, both ERT and BMT have aspects which limit their clinical applicability to humans.…”

Attenuation of ganglioside GM1 accumulation in the brain of GM1 gangliosidosis mice by neonatal intravenous gene transfer

“…Enzyme replacement therapy (ERT), 4,5 bone marrow transplantation (BMT), 1,6,7 and gene transfer 2,8 have been studied in animals and in humans with LSDs. ERT is clinically available for Gaucher disease 9 and Fabry disease 10 as medicine in many countries, and they are very effective.…”