Intravenous Enzyme Replacement Therapy for CNS Disorders

 描述（由申请人提供）：由酶缺乏引起的中枢神经系统（CNS）疾病是最具破坏性的疾病之一。对于这些，酶替代疗法（ERT）是无效的，因为酶不能穿过血脑屏障。有相当大的医疗需要的创新和非侵入性的策略，以提供功能酶到患者的大脑，从而提供显着改善生活质量。在拟议的研究中，我们制定了蛋白脂质纳米囊泡，有效地运输功能酶到动物模型的大脑与有缺陷的溶酶体酶引起的神经病变疾病。CNS对纳米囊泡的摄取通过磷脂酰丝氨酸介导的机制发生，靶向脑中的发炎细胞。我们的初步研究表明，这种静脉内酶递送系统对炎性细胞具有优异的选择性，具有很强的安全性，并且具有治疗酶缺乏动物模型（即戈谢病和戈谢相关突触核蛋白病）中神经元病症状的潜在治疗特性。完成后，预计拟议的研究将为酶或蛋白质缺乏引起的临床CNS疾病提供一种新的低风险、具有成本效益的静脉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.