Biochemical, pathological, and clinical response to transplantation of normal bone marrow cells into acid sphingomyelinase-deficient mice

Background. Acid sphingomyelinase knock-out (ASMKO) mice are a model of types A and B Niemann-Pick disease. In the present study, we evaluated whether bone marrow transplantation (BMT) carried out on newborn ASMKO mice could prevent or alter the Niemann-Pick disease phenotype, Methods. Previous work from our laboratory had shown that ASMKO mice were highly susceptible to irradiation-induced death, Therefore, we preconditioned 1-day-old ASMKO (n=35) mice with a "sublethal" dose of 200 cGy of total body irradiation before BMT. The transplantation effects were then analyzed by biochemical, pathological, and clinical approaches. Results. Engraftment ranging from 7% to 100% was achieved in 97% of the transplanted animals. Growth of the engrafted animals was improved, and their survival was increased (from a mean of 5 months to 9 months). The onset of ataxia also was delayed in most of the engrafted animals, In accordance with these observations, biochemical and pathological analysis revealed significant changes in the transplanted group as compared with nontransplanted animals. Lipid storage was reduced in several organs, and there was evidence of histologic improvement seen throughout the reticuloendothelial system, even in animals that were engrafted as low as 14%. In the central nervous system, lipid storage also was reduced, and the Purkinje cells, which are almost absent in ASMKO mice, mere present in certain areas of the transplanted animals cerebella. Conclusions. These results demonstrated that BMT could alter the pathologic phenotype in ASMKO mice, but that this procedure alone was not sufficient to elicit a complete therapeutic effect.