Physician/Scientist

Animal Models

In the early 1980s, two naturally occurring murine models of NPD were described. In 1980, Pentchev et al. described a strain of BALB/C mice with many of the characteristic NPD features, including reduced ASM activity, elevated levels of sphingomyelin and cholesterol, and clinical features such as loss of coordination, weight loss, and premature death. Shortly thereafter, Miyawaki et al. described an independent strain of C57BL/6Js mice (spm/spm) with similar biochemical and clinical findings. Since reduced ASM activity leading to the accumulation of sphingomyelin and cholesterol is characteristic of NPD in humans, both strains of mice were originally described as models for the human disorder. However, it was not clear whether these mice were models for the ASM-deficient NPD subtypes (Types A and B), or the cholesterol transport subtypes (Types C and D). In 1984, Pentchev and colleagues described the fact that the BALB/C NPD mice had an underlying defect in cholesterol transport that most resembled Type C NPD in humans. Similar studies have been performed on the spm/spm mice. The complete ASM gene was subsequently sequenced from both strains of NPD mice, and no molecular abnormalities were identified. Thus, these naturally occurring mice are models for the cholesterol transport forms of NPD, not Types A or B NPD.

In 1995, two mouse models of Types A and B NPD were independently constructed by gene targeting strategies (References). Although the precise targeting events differed in the two animals, the phenotypes were essentially identical. The NPD knock-out mice (also referred to as "ASMKO mice") appeared normal at birth and developed normally until about three months of age, at which time mild ataxia became apparent. The ataxia progressed rapidly, leading to a severe gait abnormality by five months of age. Affected animals died between the sixth and eighth months of life.

Histologic analysis of the ASMKO mice revealed that the infiltration of NPD cells throughout the RES is evident by three months of age and progresses rapidly until the time of death. In the central nervous system of affected animals, there is an almost complete absence of Purkinje cells, as well as evidence of lipid storage vacuolloes in neurons. Biochemical analysis revealed that the sphingomyelin levels were elevated in various tissues from 5- to 40-fold above those found in normal, age-matched littermates.

Thus, the NPD knock-out mice develop features of both Types A and B NPD and are an excellent model in which to evaluate various therapeutic strategies (see "Treatment of Types A and B NPD"). Towards that end, neonatal (1-4 day old) ASMKO mice were transplanted with normal bone marrow cells in order to evaluate the efficacy of BMT. An almost complete correction of the histologic and biochemical phenotype was achieved in the RES organs of these animals, providing further evidence that bone marrow transplantaton and hematopoietic stem cell-mediated gene therapy should be considered as therapeutic options for Type B NPD patients. In addition, the onset of ataxia was delayed by several months in the transplanted mice, leading to almost twofold increase in their life expectancy. This clinical result could be correlated with the recovery of the Purkinje cell layer in the transplanted animals. However, despite these positive results the treated mice still developed ataxia (albeit at a later timepoint) and died prematurely. Similar studies are currently underway in the ASMKO mice in order to evaluate enzyme replacement, hematopoietic stem cell-mediated gene therapy, and other therapeutic approaches.

It should be noted that canine and feline models of NPD also have been described. However, breeding colonies were never established, and these models were not characterized beyond their initial descriptions.