Mucopolysaccharidosis-like phenotype in feline Sandhoff disease and partial correction after AAV gene therapy
Mucopolysaccharidosis-like phenotype in feline Sandhoff disease and partial correction after AAV gene therapy
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DOI：
10.1016/j.ymgme.2015.05.003
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发表时间：
2015-09-01
影响因子：
3.8
通讯作者：
Martin, Douglas R.
中科院分区：
文献类型：
--
作者：
Gray-Edwards, Heather L.;Brunson, Brandon L.;Martin, Douglas R.
桑德霍夫病（SD）是一种由β - N - 乙酰氨基己糖苷酶突变引起的致命神经退行性疾病。婴儿期发病的桑德霍夫病患儿会出现癫痫发作、肌张力丧失和吞咽问题，最终通常在4岁左右进入植物人状态并死亡。其他症状包括脊柱后凸和心脏异常，与黏多糖贮积症极为相似。从桑德霍夫病患者分离出的成纤维细胞糖胺聚糖（GAGs）分解代谢受损。为了评估猫桑德霍夫病模型的黏多糖贮积症样特征，我们利用了放射成像、磁共振成像、超声心动图、组织病理学以及中枢神经系统和外周组织/体液的糖胺聚糖定量分析。猫桑德霍夫病模型表现出心脏瓣膜和结构异常、骨骼变化以及脊髓压迫，这些都与糖胺聚糖的积聚相符，但远不如定义人道终点（4.5±0.5个月）的严重神经系统疾病显著。颅内腺相关病毒基因治疗16周后，桑德霍夫病猫大脑皮层和肝脏中的糖胺聚糖储存被清除，但心脏、肺、骨骼肌、肾、脾、胰腺、小肠、皮肤或尿液中未被清除。糖胺聚糖储存随时间恶化，因此对于因基因治疗或其他针对原发性神经系统疾病的新疗法而大幅延长寿命的人类来说，可能成为一个重要的病理来源。由爱思唯尔公司出版。
Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme (beta-N-acetylhexosaminidase. Children with infantile onset SD develop seizures, loss of motor tone and swallowing problems, eventually reaching a vegetative state with death typically by 4 years of age. Other symptoms include vertebral gibbus and cardiac abnormalities strikingly similar to those of the mucopolysaccharidoses. Isolated fibroblasts from SD patients have impaired catabolism of glycosaminoglycans (GAGs). To evaluate mucopolysaccharidosis-like features of the feline SD model, we utilized radiography, MRI, echocardiography, histopathology and GAG quantification of both central nervous system and peripheral tissues/fluids. The feline SD model exhibits cardiac valvular and structural abnormalities, skeleta-changes and spinal cord compression that are consistent with accumulation of GAGs, but are much less prominent than the severe neurologic disease that defines the humane endpoint (4.5 +/- 0.5 months). Sixteen weeks after intracranial AAV gene therapy, GAG storage was cleared in the SD cat cerebral cortex and liver, but not in the heart, lung, skeletal muscle, kidney, spleen, pancreas, small intestine, skin, or urine. GAG storage worsens with time and therefore may become a significant source of pathology in humans whose lives are substantially lengthened by gene therapy or other novel treatments for the primary, neurologic disease. Published by Elsevier Inc.