Types A and B Niemann-Pick disease (NPD) are lysosomal storage disorders caused by deficient acid sphingomyelinase (ASM). Type A NPD is a severe neurodegenerative disease of infancy that typically causes death by three years of age. Type B NPD is characterized by the lack of neurological involvement and a phenotypic spectrum ranging from severe multisystem disease and early demise, to a milder condition of adulthood. The principal manifestations of Type B NPD include infiltrative pulmonary disease, hepatosplenomegaly, hyperlipidemia, and growth retardation and delayed puberty in children. The difficulty in differentiating between Types A and B NPD early in the disease course limits prognostic information, complicates family planning, and interferes with the selection of candidates for early therapeutic endeavors. Therefore, the ability to predict disease severity using information derived from empiric correlations between genotype and phenotype would be of significant value. Treatment for Types A and B NPD is primarily supportive, although bone marrow transplantation has been attempted with very limited success in Type B NPD patients. The therapeutic success of enzyme replacement therapy (ERT) in a related lysosomal storage disorder, Type I Gaucher disease, coupled with the demonstrated effectiveness of ERT in the Niemann-Pick mouse, provide the rationale for a clinical trial using recombinant ASM in patients with non-neuronopathic Type B NPD. The proposed studies will therefore focus on determining correlations between the clinical, radiographic and biochemical manifestations of Types A and B NPD and specific ASM mutations. In addition, the safety and effectiveness of ERT for Type B NPD will be evaluated. Thus the specific aims of the proposed research are: 1) to determine the natural history of Types A and B NPD and identify causative ASM mutations for genotype/phenotype correlations and 2) to evaluate the role of ERT for Type B NPD. An FDA-approved phase I/II clinical trial will be performed in Type B NPD patients to determine the safety and effectiveness of varying doses of intravenously administered recombinant human ASM. A series of clinical, biochemical, and pharmacological studies will be performed in order to evaluate the therapeutic effectiveness as well as the pharmacokinetics of the drug. In sum, these studies should provide important diagnostic and therapeutic information to improve the outcome of patients diagnosed with NPD.
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