Haematopoietic stem cell gene therapy with IL-1Ra rescues cognitive loss in mucopolysaccharidosis IIIA
Haematopoietic stem cell gene therapy with IL-1Ra rescues cognitive loss in mucopolysaccharidosis IIIA
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DOI：
10.15252/emmm.201911185
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发表时间：
2020-02-14
影响因子：
11.1
通讯作者：
Bigger, Brian W.
中科院分区：
文献类型：
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作者：
Parker, Helen;Ellison, Stuart M.;Bigger, Brian W.
粘多糖样变性IIIA是一种神经元病性溶酶体贮积病，其特征是硫酸乙酰肝素和其他底物在脑中积聚。患者出现行为障碍和认知能力下降，这可能是神经炎症和异常底物积累的结果。白细胞介素（IL）-1 β和白细胞介素-1受体拮抗剂（IL-1 Ra）的表达在小鼠模型和人类MPSIII患者中均显著增加。我们确定了炎性小体激活的致病机制，包括疾病特异性2-O-硫酸化硫酸乙酰肝素是通过Toll样受体4复合物引发IL-1 β应答所必需的。然而，粘多糖样变性IIIA的初级和次级储存底物，如淀粉样蛋白β，都需要激活NLRP 3炎性体和启动IL-1 β分泌。使用IL-1受体1型敲除或造血干细胞基因治疗过度表达IL-1 Ra的粘多糖样沉积症IIIA小鼠中的IL-1阻断可减少神经胶质增生并完全防止行为表型。总之，我们证明了IL-1驱动神经炎症，行为异常和认知能力下降粘多糖沉积症IIIA，突出造血干细胞基因治疗与IL-1 Ra作为一个潜在的神经元病性溶酶体疾病的治疗。
Mucopolysaccharidosis IIIA is a neuronopathic lysosomal storage disease, characterised by heparan sulphate and other substrates accumulating in the brain. Patients develop behavioural disturbances and cognitive decline, a possible consequence of neuroinflammation and abnormal substrate accumulation. Interleukin (IL)-1 beta and interleukin-1 receptor antagonist (IL-1Ra) expression were significantly increased in both murine models and human MPSIII patients. We identified pathogenic mechanisms of inflammasome activation, including that disease-specific 2-O-sulphated heparan sulphate was essential for priming an IL-1 beta response via the Toll-like receptor 4 complex. However, mucopolysaccharidosis IIIA primary and secondary storage substrates, such as amyloid beta, were both required to activate the NLRP3 inflammasome and initiate IL-1 beta secretion. IL-1 blockade in mucopolysaccharidosis IIIA mice using IL-1 receptor type 1 knockout or haematopoietic stem cell gene therapy over-expressing IL-1Ra reduced gliosis and completely prevented behavioural phenotypes. In conclusion, we demonstrate that IL-1 drives neuroinflammation, behavioural abnormality and cognitive decline in mucopolysaccharidosis IIIA, highlighting haematopoietic stem cell gene therapy treatment with IL-1Ra as a potential neuronopathic lysosomal disease treatment.