AAV-mediated gene delivery in a feline model of Sandhoff disease corrects lysosomal storage in the central nervous system.
AAV-mediated gene delivery in a feline model of Sandhoff disease corrects lysosomal storage in the central nervous system.
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DOI：
10.1177/1759091415569908
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发表时间：
2015-03
期刊：
影响因子：
4.7
通讯作者：
Martin DR
中科院分区：
文献类型：
--
作者：
Rockwell HE;McCurdy VJ;Eaton SC;Wilson DU;Johnson AK;Randle AN;Bradbury AM;Gray-Edwards HL;Baker HJ;Hudson JA;Cox NR;Sena-Esteves M;Seyfried TN;Martin DR
桑德霍夫病(SD)是一种常染色体隐性遗传性神经退行性疾病，是由于β-N-乙酰己糖胺酶(β-N-AChE)亚单位基因突变，导致溶酶体内神经节苷脂GM2不能分解而引起的。SD表现为GM2及其asialo衍生物GA2的积聚，主要分布在中枢神经系统。富含髓鞘的糖脂、脑苷脂和硫脂在SD患者中也减少，与髓鞘功能障碍相对应。目前，SD尚无治疗方法。以前的研究表明，腺相关病毒(AAV)载体介导的基因治疗在治疗SD的小鼠和猫模型中具有疗效。在这项研究中，我们用丘脑表达猫科动物Hex的AAVRH8载体联合脑室注射(Thal/icv)治疗症状前SD猫。接受治疗的动物表现出明显的神经功能和生活质量的改善，部分表现为防止或减轻了未经治疗的动物特有的全身震颤。在取自大脑皮层、小脑、丘脑和颈髓的组织样本中，Hex活性显著升高，而GM2和GA2的储存显著减少。治疗还增加了皮质和丘脑中富含髓鞘的脑苷脂和硫脂的水平。这项研究证明了AAV对猫SD的治疗潜力，并建议对人类SD患者具有类似的潜力。
Sandhoff disease (SD) is an autosomal recessive neurodegenerative disease caused by a mutation in the gene for the β-subunit of β-N-acetylhexosaminidase (Hex), resulting in the inability to catabolize ganglioside GM2 within the lysosomes. SD presents with an accumulation of GM2 and its asialo derivative GA2, primarily in the central nervous system. Myelin-enriched glycolipids, cerebrosides and sulfatides, are also decreased in SD corresponding with dysmyelination. At present, no treatment exists for SD. Previous studies have shown the therapeutic benefit of adeno-associated virus (AAV) vector-mediated gene therapy in the treatment of SD in murine and feline models. In this study, we treated presymptomatic SD cats with AAVrh8 vectors expressing feline Hex in the thalamus combined with intracerebroventricular (Thal/ICV) injections. Treated animals showed clearly improved neurologic function and quality of life, manifested in part by prevention or attenuation of whole-body tremors characteristic of untreated animals. Hex activity was significantly elevated, whereas storage of GM2 and GA2 was significantly decreased in tissue samples taken from the cortex, cerebellum, thalamus, and cervical spinal cord. Treatment also increased levels of myelin-enriched cerebrosides and sulfatides in the cortex and thalamus. This study demonstrates the therapeutic potential of AAV for feline SD and suggests a similar potential for human SD patients.