Intravenous Enzyme Replacement Therapy for CNS Disorders

 描述(申请人提供)：由酶缺乏引起的中枢神经系统(CNS)障碍是最具破坏性的疾病之一。对于这些人，酶替代疗法(ERT)是无效的，因为酶不能穿过血脑屏障。医学上有相当大的需求，需要创新的和非侵入性的策略，将功能性酶输送到患者的大脑中，从而显著提高生活质量。在这项拟议的研究中，我们设计了蛋白脂类纳米胶囊，可以有效地将功能性酶输送到患有溶酶体酶缺陷引起的神经病理性疾病的动物模型的大脑中。CNS通过磷脂酰丝氨酸介导的机制摄取纳米囊泡，靶向大脑中的炎症细胞。我们的初步研究表明，这种静脉注射酶给药系统对炎症细胞具有良好的选择性，具有很强的安全性，并具有潜在的治疗特性，可用于治疗酶缺乏动物模型(即高谢病和高谢病相关联核病)的神经病症状。完成后，这些拟议的研究有望为酶或蛋白质缺乏引起的临床中枢神经系统疾病提供一种新的低风险、成本效益高的静脉ERT。

 DESCRIPTION (provided by applicant): Central nervous system (CNS) disorders caused by enzyme deficiency are among the most devastating illnesses. For these, enzyme replacement therapy (ERT) is ineffective because enzymes cannot cross the blood brain barrier. There is a considerable medical need for innovative and non-invasive strategies to deliver functional enzymes into patients' brains, thus providing significant improvements in quality of life. In the proposed research, we formulate proteolipidic nanovesicles that effectively transport functional enzymes into the brains of animal models with neuronopathic disease caused by defective lysosomal enzymes. CNS uptake of the nanovesicles occurs via a phosphatidylserine-mediated mechanism targeting inflamed cells in the brain. Our preliminary studies demonstrate that this intravenous enzyme delivery system has excellent selectivity towards inflammatory cells, a strong safety profile, and potential therapeutic properties to treat neuronopathic symptoms in animal models of enzyme deficiency (i.e. Gaucher disease and Gaucher-related synucleinopathies). Upon completion, the proposed studies are expected to provide a new low risk, cost-effective intravenous ERT for clinical CNS disorders resulting from enzyme or protein deficiency.