Genzyme Corporation, Framingham, MA, USA.
Exp Neurol. 2011 Oct;231(2):261-71. doi: 10.1016/j.expneurol.2011.06.019. Epub 2011 Jul 14.
One treatment approach for lysosomal storage diseases (LSDs) is the systemic infusion of recombinant enzyme. Although this enzyme replacement is therapeutic for the viscera, many LSDs have central nervous system (CNS) components that are not adequately treated by systemic enzyme infusion. Direct intracerebroventricular (ICV) infusion of a high concentration of recombinant human acid sphingomyelinase (rhASM) into the CNS over a prolonged time frame (hours) has shown therapeutic efficacy in a mouse model of Niemann-Pick A (NP/A) disease. To evaluate whether such an approach would translate to a larger brain, rhASM was infused into the lateral ventricles of both rats and Rhesus macaques, and the resulting distribution of enzyme characterized qualitatively and quantitatively. In both species, ICV infusion of rhASM resulted in parenchymal distribution of enzyme at levels that were therapeutic in the NP/A mouse model. Enzyme distribution was global in nature and exhibited a relatively steep gradient from the cerebrospinal fluid compartment to the inner parenchyma. Additional optimization of an ICV delivery approach may provide a therapeutic option for LSDs with neurologic involvement.
溶酶体贮积症（LSD）的一种治疗方法是全身输注重组酶。尽管这种酶替代疗法对内脏有效，但许多 LSD 都有中枢神经系统（CNS）成分，而全身酶输注并不能充分治疗这些成分。将高浓度的重组人酸性鞘磷脂酶（rhASM）通过延长时间（数小时）直接脑室内（ICV）输注到 CNS 中，已在尼曼-匹克 A（NP/A）病的小鼠模型中显示出治疗效果。为了评估这种方法是否适用于更大的脑，rhASM 被输注到大鼠和恒河猴的侧脑室中，并定性和定量地描述了由此产生的酶分布。在这两种物种中，ICV 输注 rhASM 导致实质内分布的酶水平与 NP/A 小鼠模型中的治疗水平相当。酶的分布具有全球性，并且从脑脊液隔室到内部实质表现出相对陡峭的梯度。对 ICV 给药方法的进一步优化可能为具有神经受累的 LSD 提供一种治疗选择。
