Cisterna magna delivery of therapeutic lysosomal enzyme to correct CNS pathology in lysosomal storage disorders

LSD是一种遗传性疾病，每7700名澳大利亚儿童中就有1名患有LSD;所有儿童都有共同的身体症状，包括心脏和呼吸困难、关节僵硬、骨骼畸形、头部增大和特征性面部外观。三分之二的患者也会患上脑部疾病。溶酶体是人体每个细胞的组成部分;它的作用是分解和清除细胞中的废物。这涉及一系列按顺序起作用的蛋白质（酶）。当溶酶体缺乏这条链中一种蛋白质的活性时，LSD就会产生。蛋白质活性的丧失会损害废物去除过程。废物开始“储存”，堵塞细胞并干扰其正常功能。这会引起破坏性的症状，随着储存量的增加，这些症状会随着时间的推移而恶化。LSD中的脑部疾病对儿童有深远的影响：智力下降，他们变得过度活跃和侵略性，并逐渐失去学习技能（例如走路，说话）和控制身体功能的能力。人工合成的蛋白质被成功地用于静脉注射治疗某些LSD。然而，由于大脑周围有一层保护屏障，它无法进入大脑。该项目测试了一种将蛋白质输送到大脑以减少和阻止废物积聚的方法。它涉及使用用于治疗其他疾病的技术将人工制造的蛋白质注射到大脑和脊髓周围的液体中。这种方法可能是我们治疗受影响儿童的身体和大脑的最快方法。我们已经诊断出动物模型，他们出生时患有LSD和脑部疾病，称为MPS IIIA。它们的症状与人类在疾病过程中看到的症状相似，使它们成为本项目研究的理想对象。该项目的成功将使我们能够将这种治疗方法推向人体试验。

Lysosomal storage disorders (LSD) are inherited diseases that affect about 1 in 7700 Australian children; all share common physical symptoms include heart and breathing difficulties, stiff joints, skeletal deformities, enlarged head, and a characteristic facial appearance. Two-thirds of patients will also develop brain disease. The lysosome is a component of each cell in the human body; its role it is to break down and remove waste from the cell. This involves a series of proteins (enzymes) that act in sequence. A LSD arises when the lysosome lacks the activity of one protein in this chain. The loss of protein activity impairs the waste removal process. Waste begins to 'store', clogging the cell and interfering with its usual functions. This gives rise to devastating symptoms that worsen over time as storage increases. Brain disease in LSD has profound effects on the child: mental capacity declines, they become hyperactive and aggressive and progressively lose learned skills (e.g. walking, talking) and ability to control bodily functions. Artifically made protein is being successfully used to treat some LSD via intravenous injection. However, it is not able to access the brain because of a protective barrier that surrounds it. This project tests a method to deliver protein to the brain to reduce and stop waste build-up. It involves the injection of artificially made protein into the fluid surrounding the brain and spinal cord using techniques being used to treat other diseases. This method is likely to be the quickest way in which we can treat both the body AND the brain of an affected child. We have diagnosed animal models who were born with a LSD with brain disease, called MPS IIIA. Their symptoms are similar to that seen in humans over the course of the disease, making them ideal for study in this project. Success in this project will allow us to advance this treatment to human trials.