Acid sphingomyelinase deficient mice: a model of types A and B Niemann–Pick disease

Abstract

Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM). An animal model of NPD has been created by gene targeting. In affected animals, the disease followed a severe, neurodegenerative course and death occurred by eight months of age. Analysis of these animals showed their tissues had no detectable ASM activity, the blood cholesterol levels and sphingomyelin in the liver and brain were elevated, and atrophy of the cerebellum and marked deficiency of Purkinje cells was evident. Microscopic analysis revealed 'NPD cells' in reticuloendothelial organs and characteristic NPD lesions in the brain. Thus, the ASM deficient mice should be of great value for studying the pathogenesis and treatment of NPD, and for investigations into the role of ASM in signal transduction and apoptosis.

Hematopoietic stem cell gene therapy leads to marked visceral organ improvements and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann–Pick disease

“…Untreated ASMKO mice have Ͻ1% of normal WBC ASM activity. 9 Beginning at 1 month and up until the fifth month after transplant, the levels of WBC ASM activity in the treated animals progressively increased, and stabilized thereafter. However, no direct correlation between the WBC ASM activity and survival (see Figure Figure 1 2, below) was observed when individual animals were analyzed.…”

“…9,18,25 It is also the likely cause of the progressive ataxia, which eventually leads to death. It has been reported that ceramide is an essential factor required for survival of cerebella PC neurons.…”

“…Note that the levels of ASM activity in the spleens, livers and lungs of the treated ASMKO animals was approximately 90, 65 and 40% of normal, respectively, significantly above the values found in untreated ASMKO animals. 9 (P value when comparing ASM activities in these tissues between treated and untreated ASMKO mice was Ͻ0.0001.) In contrast, the levels of ASM activity found in the brains, hearts and kidneys of the treated animals were not statistically greater than those found in untreated animals (P values Ͼ0.1).…”

“…9 ASMKO male mice (8-12 weeks old) were used as the source of donor cells. To obtain nucleated bone marrow cells, donor animals were pretreated with 5FU (150 mg/kg) 48 h before death by cervical dislocation.…”

“…9,10 The clinical, biochemical and pathological features of the ASM-deficient (ASMKO) mice mimic human types A and B NPD, offering the opportunity to gain new insights into the pathogenesis of the disease and to develop and evaluate new therapeutic approaches.…”