Enzyme replacement in murine mucopolysaccharidosis type VII: Neuronal and glial response to beta-glucuronidase requires early initiation of enzyme replacement therapy

We have previously shown that mucopolysaccharidosis type VII (MPS VII) mice receiving six weekly injections of recombinant P-glucuronidase from birth had improved cognitive ability and reduced central nervous system lysosomal storage. However, a single P-glucuronidase injection at 5 wk of age did no t comet neuronal storage. We define the age at which central nervous system storage in MPS VII mice becomes resistant to P-glucuronidase therapy and d etermine the effect of enzyme on other tissues by comparing the histology o f mice begun on therapy at various times after birth. MPS VII mice received injections on the day of birth and then weekly for 5 wk with 16 000U/g P-g lucuronidase had reduced lysosomal storage in brain. The same therapy begun on d 14 of life or thereafter failed to comet neuronal storage, even when treatment was continued for six doses. Glial responsiveness or accessibilit y to enzyme also depended on early treatment. In contrast, leptomeningeal, osteoblast, and retinal pigment epithelial storage reduction depended on en zyme dose rather than age at initiation of therapy. Fixed tissue macrophage storage was reduced in all treated MP-S VII mice, even those receiving a s ingle dose. These observations indicate that fixed tissue macrophages in MP S VII mice remain sensitive to enzyme replacement therapy well into adultho od although neurons are responsive or accessible to enzyme therapy early in lift. Because early initiation of enzyme replacement is important to achie ve a central nervous system response, these studies emphasize the importanc e of newborn screening fur lysosomal storage diseases so that early treatme nt can maximize the likelihood of a favorable therapeutic response.