Miranda S R, He X, Simonaro C M, Gatt S, Dagan A, Desnick R J, Schuchman E H
Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.
FASEB J. 2000 Oct;14(13):1988-95. doi: 10.1096/fj.00-0014com.
An inherited deficiency of acid sphingomyelinase (ASM) activity results in the Type A and B forms of Niemann-Pick disease (NPD). Using the ASM-deficient mouse model (ASMKO) of NPD, we evaluated the efficacy of enzyme replacement therapy (ERT) for the treatment of this disorder. Recombinant human ASM (rhASM) was purified from the media of overexpressing Chinese Hamster ovary cells and i.v. injected into 16 five-month-old ASMKO mice at doses of 0.3, 1, 3, or 10 mg/kg every other day for 14 days (7 injections). On day 16, the animals were killed and the tissues were analyzed for their sphingomyelin (SPM) content. Notably, the SPM levels were markedly reduced in the hearts, livers, and spleens of these animals, and to a lesser degree in the lungs. Little or no substrate depletion was found in the kidneys or brains. Based on these results, three additional 5-month-old ASMKO animals were injected every other day with 5 mg/kg for 8 days (4 injections) and killed on day 10 for histological analysis. Consistent with the biochemical results, marked histological improvements were observed in the livers, spleens, and lungs, indicating a reversal of the disease pathology. A group of 10 ASMKO mice were then i.v. injected once a week with 1 mg/kg rhASM for 15 wk, starting at 3 wk of age. Although anti-rhASM antibodies were produced in these mice, the antibodies were not neutralizing and no adverse effects were observed from this treatment. Weight gain and rota-rod performance were slightly improved in the treated animals as compared with ASMKO control animals, but significant neurological deficits were still observed and their life span was not extended by ERT. In contrast with these CNS results, striking histological and biochemical improvements were found in the reticuloendothelial system organs (livers, spleens, and lungs). These studies indicate that ERT should be an effective therapeutic approach for Type B NPD, but is unlikely to prevent the severe neurodegeneration associated with Type A NPD.
酸性鞘磷脂酶（ASM）活性的遗传性缺乏会导致A型和B型尼曼-匹克病（NPD）。我们使用NPD的ASM缺陷小鼠模型（ASMKO），评估了酶替代疗法（ERT）治疗这种疾病的疗效。重组人ASM（rhASM）从过表达的中国仓鼠卵巢细胞培养基中纯化出来，并通过静脉注射给予16只5月龄的ASMKO小鼠，剂量为0.3、1、3或10mg/kg，每隔一天注射一次，共14天（7次注射）。在第16天，处死动物并分析组织中的鞘磷脂（SPM）含量。值得注意的是，这些动物的心脏、肝脏和脾脏中的SPM水平显著降低，肺部的降低程度较小。在肾脏或大脑中几乎没有发现底物消耗。基于这些结果，另外3只5月龄的ASMKO动物每隔一天注射5mg/kg，共8天（4次注射），并在第10天处死进行组织学分析。与生化结果一致，在肝脏、脾脏和肺部观察到明显的组织学改善，表明疾病病理得到逆转。然后，一组10只ASMKO小鼠从3周龄开始，每周静脉注射一次1mg/kg rhASM，共15周。尽管这些小鼠产生了抗rhASM抗体，但这些抗体没有中和作用，并且该治疗未观察到不良反应。与ASMKO对照动物相比，治疗动物的体重增加和转棒性能略有改善，但仍观察到明显的神经功能缺陷，并且ERT没有延长它们的寿命。与这些中枢神经系统结果相反，在网状内皮系统器官（肝脏、脾脏和肺部）中发现了显著的组织学和生化改善。这些研究表明，ERT应该是治疗B型NPD的有效治疗方法，但不太可能预防与A型NPD相关的严重神经退行性变。
