Neuro-inflammation and treatment in GM2 gangliosidosis

描述（由申请方提供）：泰-萨二氏病和桑德霍夫病是由β-氨基己糖苷酶缺乏引起的遗传性溶酶体贮积症。受影响的患者表现为神经变性、精神和运动退化、肌肉松弛、失明、构音障碍、热敏感性受损、痴呆增加和黄斑中的樱桃红点。根据临床严重程度，患者可能会达到植物人状态，然后早在2-4岁时死亡。脑、小脑、脑干、脊髓、三叉神经和脊根神经节的神经元显示储存有过量GM 2神经节苷脂的肿胀空泡化胞体，导致异常神经元功能、小胶质细胞活化和脑炎症。基于这些观察结果，我们假设继发于GM 2神经元神经节苷脂沉积的小胶质细胞活化和神经炎症有助于神经变性和疾病的发展。为了验证这一假设，我们建议在GM 2神经节苷脂沉积症（hexB-/-敲除）小鼠模型中研究神经元储存及其对小胶质细胞/单核细胞/巨噬细胞系统的影响。首先，我们将通过选择性地从β-氨基己糖苷酶缺乏中拯救神经元来确定GM 2神经节苷脂沉积症在脑炎症中的作用。其次，我们将研究外周血单核细胞在GM 2神经节苷脂沉积症中的作用，通过抑制单核细胞/巨噬细胞浸润到大脑中。随后，我们将用能够表达人β-氨基己糖苷酶的两个亚基的治疗基因β-Hex转染骨髓来源的细胞，并以类似于骨髓移植后描述的方式评估它们在减轻疾病发展方面的功效。在最后一个具体的目标，我们将确定是否β-氨基己糖苷酶基因治疗腹腔注射给hexB-/- P2新生儿可以有效地激活神经元，神经胶质细胞和外周血单核细胞与治疗基因betaHex。通过这种更多的治疗，我们预期GM 2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.