Niemann-Pick A disease (NPD-A) is caused by a deficiency of acid sphingomyelinase (ASM) leading to the intracellular accumulation of sphingomyelin and cholesterol in lysosomes. We evaluated the effects of direct intraparenchymal brain injections of purified recombinant human ASM (hASM) at correcting the storage pathology in a mouse model of NPD-A (ASMKO). Different doses (0.1 ng to 10 mug of hASM) were injected into the right hemisphere of the hippocampus and thalamus of 12- to 14-week-old ASMKO mice. Immunohistochemical analysis after 1 week indicated that animals treated with greater than 1 mug hASM/site showed detectable levels of enzyme around the injected regions. However, localized clearance of sphingomyelin and cholesterol storage were observed in animals administered lower doses of enzyme, starting at 100 ng hASM/site. Areas of correction were also noted at distal sites such as in the contralateral hemispheres. Indications of storage re-accumulation were seen after 2 weeks post-injection. Injections of hASM did not cause any significant cell infiltration, astrogliosis, or microglial activation. These results indicate that intraparenchymal injection of hASM is associated with minimal toxicity and can lead to regional reductions in storage pathology in the ASMKO mouse.
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