Genzyme Corporation, Framingham, Massachusetts, United States of America.
PLoS One. 2011 Jan 25;6(1):e16313. doi: 10.1371/journal.pone.0016313.
Niemann-Pick A (NPA) disease is a lysosomal storage disorder (LSD) caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously, we reported that biochemical and functional abnormalities observed in ASM knockout (ASMKO) mice could be partially alleviated by intracerebroventricular (ICV) infusion of hASM. We now show that this route of delivery also results in widespread enzyme distribution throughout the rat brain and spinal cord. However, enzyme diffusion into CNS parenchyma did not occur in a linear dose-dependent fashion. Moreover, although the levels of hASM detected in the rat CNS were determined to be within the range shown to be therapeutic in ASMKO mice, the absolute amounts represented less than 1% of the total dose administered. Finally, our results also showed that similar levels of enzyme distribution are achieved across rodent species when the dose is normalized to CNS weight as opposed to whole body weight. Collectively, these data suggest that the efficacy observed following ICV delivery of hASM in ASMKO mice could be scaled to CNS of the rat.
尼曼-匹克 A 病（NPA）是一种溶酶体贮积症（LSD），由酸性鞘磷脂酶（ASM）活性缺乏引起。此前，我们报道过 ASM 敲除（ASMKO）小鼠中观察到的生化和功能异常可通过脑室内（ICV）输注 hASM 部分缓解。我们现在表明，这种给药途径还可导致酶在整个大鼠脑和脊髓中广泛分布。然而，酶并未以线性剂量依赖性方式扩散到中枢神经系统实质中。此外，尽管在大鼠中枢神经系统中检测到的 hASM 水平在 ASMKO 小鼠中显示出治疗效果的范围内，但绝对数量不到给药总量的 1%。最后，我们的结果还表明，当根据中枢神经系统重量而不是全身重量对剂量进行归一化时，啮齿动物物种之间可实现类似水平的酶分布。总的来说，这些数据表明，在 ASMKO 小鼠中通过 ICV 递送 hASM 观察到的疗效可以扩展到大鼠的中枢神经系统。
