Bone marrow transplantation in acid sphingomyelinase-deficient mice: engraftment and cell migration into the brain as a function of radiation, age, and phenotype.

Types A and B Niemann-Pick disease (NPD) result from the deficient activity of the lysosomal hydrolase, acid sphingomyelinase (ASM). A long-term goal of our research is to evaluate the effects of bone marrow transplantation (BMT) and hematopoietic stem cell gene therapy (HSCGT) on the NPD phenotype. As an initial step toward this goal, we have undertaken a study aimed at optimizing hematopoietic cell engraftment in acid sphingomyelinase "knock-out" (ASMKO) mice. Several parameters were analyzed, including the effects of radiation and donor cell number on survival and engraftment of newborn and adult animals, the number of donor cells detected in the brain posttransplantation, and the levels of ASM activity achieved in the brain. A total of 202 ASMKO and normal animals were transplanted and studied, and the overall conclusions were: (1) newborn ASMKO animals were more susceptible to radiation-induced mortality than normal animals, (2) at low radiation doses, increasing the donor cell number improved engraftment, while this was less evident at the higher radiation doses, (3) engraftment was easier to achieve in normal as compared with ASMKO animals, (4) among newborn transplants, the number of donor cells detected in the brain was directly correlated with engraftment in the blood, (5) more donor cells were detected in the brains of newborn ASMKO animals as opposed to newborn normal animals, and (6) no donor cells were found in the brains of animals transplanted as adults, including those that were highly engrafted in the blood. These results provide important information regarding the design of future BMT and HSCGT studies in ASMKO mice and other mouse models and demonstrate the potential of altering the NPD phenotype by these therapeutic strategies.