转基因拯救震颤小鼠的克拉伯病。

Transgenic rescue of Krabbe disease in the twitcher mouse.

作者信息

De Gasperi R, Friedrich V L, Perez G M, Senturk E, Wen P H, Kelley K, Elder G A, Gama Sosa M A

机构信息

Department of Psychiatry, Mount Sinai School of Medicine of New York University, New York, NY, USA.

出版信息

Gene Ther. 2004 Aug;11(15):1188-94. doi: 10.1038/sj.gt.3302282.

DOI:10.1038/sj.gt.3302282

PMID:15164096

Abstract

The twitcher mouse is a natural model of Krabbe disease caused by galactocerebrosidase (GALC) deficiency. Previous attempts at rescuing the twitcher mouse by bone marrow transplantion, viral transduction, or transgenesis were only partially successful. Here, we report the transgenic (tg) rescue of the twitcher mouse with a BAC clone harboring the entire GALC. The twi/twi/hGALC tg mice exhibited growth, motor function, and fertility similar to those of nonaffected animals. These animals had normal levels of GALC activity in brain and were free of the typical twitcher demyelinating pathology. Surprisingly, GALC expression in twi/twi hGALC tg kidneys was low and galactocerebroside storage was only partially cleared. Nonetheless, these mice have been maintained for over 1 year without any sign of disease. Since pathological damage associated with GALC deficiency is confined to the nervous system, our work represents the first successful rescue of the twitcher mouse and opens the possibility of developing novel therapeutic approaches.

摘要

颤抖小鼠是由半乳糖脑苷脂酶（GALC）缺乏引起的克拉伯病的天然模型。此前通过骨髓移植、病毒转导或转基因来拯救颤抖小鼠的尝试仅取得了部分成功。在此，我们报告了用携带完整GALC的BAC克隆对颤抖小鼠进行转基因（tg）拯救。twi/twi/hGALC转基因小鼠的生长、运动功能和生育能力与未受影响的动物相似。这些动物大脑中的GALC活性水平正常，且没有典型的颤抖小鼠脱髓鞘病理特征。令人惊讶的是，twi/twi hGALC转基因小鼠肾脏中的GALC表达较低，半乳糖脑苷脂的储存仅得到部分清除。尽管如此，这些小鼠已经维持了1年多且没有任何疾病迹象。由于与GALC缺乏相关的病理损伤仅限于神经系统，我们的工作代表了首次成功拯救颤抖小鼠，并为开发新的治疗方法开辟了可能性。