Shen J S, Watabe K, Ohashi T, Eto Y
Department of Gene Therapy, Institute of DNA Medicine, Tokyo, Japan.
Gene Ther. 2001 Jul;8(14):1081-7. doi: 10.1038/sj.gt.3301495.
Twitcher mouse is a murine model of human globoid cell leukodystrophy (Krabbe disease), which is characterized by a genetic deficiency in galactocerebrosidase (GALC) activity. The nervous system is affected early and severely by demyelination in the white matter. So far, there is no effective treatment for Krabbe disease except bone marrow transplantation (BMT). However, BMT has inherent limitations such as unavailability of donors and graft-versus-host disease. In this study, we injected recombinant adenovirus encoding GALC into the lateral ventricle of twitcher mice at postnatal day 0 (PND 0) and the therapeutic effects were evaluated. Our results showed slight, but significant improvements in motor functions, body weight and twitching and a prolonged life span. In brain, GALC activity was increased to 15% that of normal littermates and psychosine concentration was decreased to 55% that of untreated twitcher mice at PND 15. The number of PAS-positive globoid cells in brain stem was also reduced significantly at PND 35. In contrast, when adenoviruses were injected to the twitcher mice at PND 15, almost no improvements were observed. These results demonstrate that the timing of treatment may be of great importance in Krabbe disease.
颤抖小鼠是人类球形细胞脑白质营养不良症（克拉伯病）的一种小鼠模型，其特征是半乳糖脑苷脂酶（GALC）活性存在遗传缺陷。神经系统早期就会受到严重影响，白质发生脱髓鞘病变。到目前为止，除了骨髓移植（BMT）外，克拉伯病尚无有效的治疗方法。然而，骨髓移植存在固有的局限性，如供体不可得和移植物抗宿主病。在本研究中，我们在出生后第0天（PND 0）将编码GALC的重组腺病毒注入颤抖小鼠的侧脑室，并评估其治疗效果。我们的结果显示，运动功能、体重和抽搐症状有轻微但显著的改善，寿命延长。在大脑中，PND 15时GALC活性增加至正常同窝小鼠的15%，半乳糖鞘氨醇浓度降至未治疗的颤抖小鼠的55%。在PND 35时，脑干中PAS阳性球形细胞的数量也显著减少。相比之下，在PND 15时将腺病毒注入颤抖小鼠，几乎未观察到任何改善。这些结果表明，治疗时机在克拉伯病中可能非常重要。
