Neuro-inflammation and treatment in GM2 gangliosidosis

描述(申请人提供)：泰-萨克斯和桑德霍夫病是由β-己糖苷酶缺乏引起的遗传性溶酶体储存障碍。受影响的患者出现神经退化、精神和运动退化、肌肉松弛、失明、构音障碍、热敏感度受损、痴呆症增加以及眼睛黄斑出现樱桃红色斑点。根据临床严重程度的不同，患者可能在2-4岁时达到植物状态，然后死亡。脑、小脑、脑干、脊髓、三叉神经节和脊神经节的神经元出现肿胀的空泡化核膜，大量GM2神经节苷脂储存，导致神经元功能异常、小胶质细胞激活和脑部炎症。基于这些观察，我们假设GM2神经节苷脂沉积症继发的小胶质细胞激活和神经炎症有助于神经退行性变和疾病的发展。为了验证这一假说，我们建议在GM2神经节苷脂沉积症的小鼠模型中研究神经元存储及其对小胶质细胞/单核/巨噬细胞系统的影响。首先，我们将通过选择性地从β-己糖苷酶缺乏症中拯救神经元来确定GM2神经节苷脂在脑炎症中的作用。其次，我们将通过抑制单核/巨噬细胞向脑内的渗透来研究外周血单核细胞在GM2神经节苷脂增多症中的作用。随后，我们将转导带有治疗性基因BetaHex的骨髓来源细胞，该基因能够表达人β-己糖苷酶的两个亚单位，并以类似于骨髓移植后描述的方式评估它们在减缓疾病发展方面的有效性。在最后一个特定的目标中，我们将确定通过治疗基因betaHex，将β-己糖苷酶基因治疗应用于hexB-/-P2新生儿是否能有效地转导神经元、神经胶质细胞和外周血单核细胞。通过这种更多的治疗，我们预计GM2储存和神经炎症的解决最终导致疾病的临床表型的改善。

DESCRIPTION (provided by applicant): Tay-Sachs and Sandhoff disease are inherited lysosomal storage disorders resulting from beta-hexosaminidase deficiency. Affected patients present with neurodegeneration, mental and motor deterioration, muscular flaccidity, blindness, dysarthria, impaired thermal sensitivity, increasing dementia and cherry-red spots in the macula of the eye. Depending on the clinical severity patients may reach a vegetative state followed by death as early as 2-4 years of life. The neurons of the brain, cerebellum, brain stem, spinal cord, trigeminal and spinal root ganglia display swollen vacuolated perikarya stored with excessive amounts of GM2 ganglioside, leading to aberrant neuronal function, microglia activation and brain inflammation. Based on these observations, we hypothesize that microglia activation and neuro-inflammation secondary to GM2 neuronal gangliosidosis contributes to neurodegeneration and disease development. To test this hypothesis, we propose to investigate neuronal storage and its effects on the microglia/monocyte/macrophage system in a mouse model of GM2 gangliosidosis (hexB-/-knockout). First, we will determine the role of GM2 gangliosidosis in brain inflammation by selectively rescuing neurons from beta-hexosaminidase deficiency. Second, we will investigate the role of peripheral blood mononuclear cells in GM2 gangliosidosis by inhibiting monocyte/macrophage infiltration into the brain. Subsequently, we will transduce bone marrow derived-cells with the therapeutic gene betaHex, capable of expressing both subunits of the human beta-hexosaminidase, and evaluate their efficacy in attenuating disease development in a fashion similar to that described after bone marrow transplantation. In the last specific aim, we will determine whether beta-hexosaminidase gene therapy administered intraperitoneally to hexB-/- P2 neonates can effectively transduce neurons, glia and peripheral blood mononuclear cells with the therapeutic gene betaHex. With this more of therapy we anticipate a resolution of GM2 storage and neuro-inflammation ultimately leading to amelioration of the clinical phenotype of the disease.