We have previously shown that
mucopolysaccharidosis type VII (MPS VII) mice receiving six weekly
injections of recombinant
beta-glucuronidase from birth had improved cognitive ability and reduced central nervous system lysosomal storage. However, a single
beta-glucuronidase injection at 5 wk of age did not correct neuronal storage. We define the age at which central nervous system storage in MPS VII mice becomes resistant to
beta-glucuronidase therapy and determine the effect of
enzyme on other tissues by comparing the histology of 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
beta-glucuronidase had reduced lysosomal storage in brain. The same
therapy begun on d 14 of life or thereafter failed to correct neuronal storage, even when treatment was continued for six doses. Glial responsiveness or accessibility to
enzyme also depended on early treatment. In contrast, leptomeningeal, osteoblast, and
retinal pigment epithelial storage reduction depended on
enzyme dose rather than age at initiation of
therapy. Fixed tissue macrophage storage was reduced in all treated MPS VII mice, even those receiving a single dose. These observations indicate that fixed tissue macrophages in MPS VII mice remain sensitive to
enzyme replacement therapy well into adulthood although neurons are responsive or accessible to
enzyme therapy early in life. Because early initiation of
enzyme replacement is important to achieve a central nervous system response, these studies emphasize the importance of newborn screening for
lysosomal storage diseases so that early treatment can maximize the likelihood of a favorable therapeutic response.