TREATMENT OF MURINE MUCOPOLYSACCHARIDOSIS TYPE-VII BY SYNGENEIC BONE-MARROW TRANSPLANTATION IN NEONATES

BACKGROUND: Bone marrow transplantation (BMT) proved an effective ther apy for murine mucopolysaccharidosis type VII (MPS VII) in adult gus(m ps)/gus(mps) mice with well developed clinical and pathologic characte ristics of the disease. MPS VII mice transplanted as adults had a mark ed decrease in lysosomal storage material in many organs, although not in the skeleton and brain (1). Since untreated newborn MPS VII mice a ppear normal and have minimal lysosomal storage material detectable mi croscopically, we postulated that BMT in newborn mice might prevent th e subsequent accumulation of storage material. EXPERIMENTAL DESIGN: On e-day-old mutant and phenotypically normal mice were exposed to 2, 4, 6 and 8 Gray and then injected intravenously with syngeneic bone marro w cells from homozygous normal females. Transplanted mice were examine d biochemically and microscopically at 10 weeks and 10 months of age. RESULTS: Newborn mice receiving BMT lived longer than untreated mutant s, had less severe facial dysmorphism, and better mobility. Beta-Glucu ronidase activity in liver, spleen, kidney and brain increased with in creasing radiation dose. The secondary elevations of alpha-galactosida se and beta-hexosaminidase observed in MPS VII, were significantly red uced 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 p igment epithelium and caused a slight decrease in neuronal storage at high radiation dose. Radiation dose dependent cerebellar and retinal d ysplasia and long bone growth retardation was observed when the therap y was initiated in newborn mice but not when the animals were transpla nted as adults. CONCLUSIONS: BMT is a more effective therapy for MPS V II when it is performed at birth rather than in adults. Alternate mean s of ablating host hematopoietic stem cells should be employed as a pr etreatment for BMT due to the severe side effects of radiation on newb orns.