来源:生物谷 2009-1-29 


NieMann- Pick 病(Niemann –Pick’sudisease) 是一种按单纯孟德尔隐性遗传规律遗传的疾病。它让胆固醇在细胞中积累,导致大脑损伤和死亡。主要有关酶缺乏引起神经髓鞘磷脂、胆固醇及其他磷脂在肝、脾的内皮细胞及脑部沉积引起。临床表现有肝、脾肿大,神经系统症状,聋、盲及智力低下。视网膜黄斑部有磷脂沉积者亦可见樱红斑。本病为进行性,多在发病数年后死亡。


最近,科学家开发了一种可能治疗小鼠的C型Niemann-Pick病(NPC)的化合物。


美国德克萨斯大学西南医学院John Dietschy及其同事发现仅注射一次称为CYCLO的化合物就可以释放出在细胞中积累的胆固醇,并逆转小鼠模型的这种病。健康细胞从血流中吸收胆固醇,并把这种化合物结合到细胞膜中,作为类固醇激素和胆汁酸的基本成分。患NPC的人类和小鼠有一种遗传突变,它阻止了胆固醇正确地通过细胞,这导致了胆固醇的积累。这组作者向NPC小鼠注射了仅仅一剂CYCLO,然后发现了接受治疗的小鼠开始像健康小鼠那样处理胆固醇。甚至过了49天,这只注射了一剂CYCLO的小鼠比未经治疗的同类小鼠的胆固醇负担显著降低,而且改善了肝功能、降低了神经变性,并且寿命显著更长。这组作者得出结论说,这种疗法暂时地让胆固醇运输缺陷正常化,而且可能有潜力成为NPC患者的一种疗法。(生物谷Bioon.com)


生物谷推荐原始出处:


PNAS Published online before print January 26, 2009, doi: 10.1073/pnas.0810895106


Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1−/− mouse


Benny Liua, Stephen D. Turleya, Dennis K. Burnsb, Anna M. Millerc, Joyce J. Repaac and John M. Dietschya1


aDepartments of aInternal Medicine, 
bPathology, and 
cPhysiology, University of Texas Southwestern Medical Center, Dallas, TX 75390


Abstract


Niemann-Pick type C disease is largely attributable to an inactivating mutation of NPC1 protein, which normally aids movement of unesterified cholesterol (C) from the endosomal/lysosomal (E/L) compartment to the cytosolic compartment of cells throughout the body. This defect results in activation of macrophages in many tissues, progressive liver disease, and neurodegeneration. In the npc1−/− mouse, a model of this disease, the whole-animal C pool expands from 2,082 to 4,925 mg/kg body weight (bw) and the hepatic C pool increases from 132 to 1,485 mg/kg bw between birth and 49 days of age. A single dose of 2-hydroxypropyl-β-cyclodextrin (CYCLO) administered at 7 days of age immediately caused this sequestered C to flow from the lysosomes to the cytosolic pool in many organs, resulting in a marked increase in cholesteryl esters, suppression of C but not fatty acid synthesis, down-regulation of genes controlled by sterol regulatory element 2, and up-regulation of many liver X receptor target genes. There was also decreased expression of proinflammatory proteins in the liver and brain. In the liver, where the rate of C sequestration equaled 79 mg·d−1·kg−1, treatment with CYCLO within 24 h increased C movement out of the E/L compartment from near 0 to 233 mg·d−1·kg−1. By 49 days of age, this single injection of CYCLO resulted in a reduction in whole-body C burden of >900 mg/kg, marked improvement in liver function tests, much less neurodegeneration, and, ultimately, significant prolongation of life. These findings suggest that CYCLO acutely reverses the lysosomal transport defect seen in NPC disease.