Treatment of murine mucopolysaccharidosis type VII by syngeneic bone marrow transplantation in neonates.

BACKGROUND

Bone marrow transplantation (BMT) proved an effective therapy for murine mucopolysaccharidosis type VII (MPS VII) in adult gusmps/gusmps mice with well developed clinical and pathologic characteristics of the disease. MPS VII mice transplanted as adults had a marked decrease in lysosomal storage material in many organs, although not in the skeleton and brain (1). Since untreated newborn MPS VII mice appear normal and have minimal lysosomal storage material detectable microscopically, we postulated that BMT in newborn mice might prevent the subsequent accumulation of storage material.

EXPERIMENTAL

DESIGN

One-day-old mutant and phenotypically normal mice were exposed to 2, 4, 6 and 8 Gray and then injected intravenously with syngeneic bone marrow cells from homozygous normal females. Transplanted mice were examined biochemically and microscopically at 10 weeks and 10 months of age.

RESULTS

Newborn mice receiving BMT lived longer than untreated mutants, had less severe facial dysmorphism, and better mobility. beta-Glucuronidase activity in liver, spleen, kidney and brain increased with increasing radiation dose. The secondary elevations of alpha-galactosidase and beta-hexosaminidase observed in MPS VII, were significantly reduced in liver and spleen in all radiation groups. Treated mutants had less histologic evidence of lysosomal storage disease in bones, joints and periarticular tissue as compared with untreated mutants. Neonatal BMT also reduced storage in the leptomeninges, ependyma and retinal pigment epithelium and caused a slight decrease in neuronal storage at high radiation dose. Radiation dose dependent cerebellar and retinal dysplasia and long bone growth retardation was observed when the therapy was initiated in newborn mice but not when the animals were transplanted as adults.

CONCLUSIONS

BMT is a more effective therapy for MPS VII when it is performed at birth rather than in adults. Alternate means of ablating host hematopoietic stem cells should be employed as a pretreatment for BMT due to the severe side effects of radiation on newborns.