Nanoparticle Distributed Intravenous Enzyme Replacement Therapy (NanoDIVERT)

项目摘要 酶替代疗法（ERT）已成功地改善非糖尿病患者的症状， 神经性溶酶体贮积症（LSD），使其成为这些罕见的，孤儿， 遗传病基本上，患者接受内源性酶的静脉内（IV）输注， 以低浓度存在，完全缺失或错误折叠，因此由于它们的遗传缺陷而功能失调。 疾病尽管ERT在临床上有希望，但它不能用于治疗50-70%的中枢神经系统LSD。 由于阻止重组酶通过的血脑屏障（BBB）引起的系统表现 从血液进入大脑这些疾病之一和本提案的重点，GM 1神经节苷脂沉积症， 来自GLB 1的变体，导致溶酶体β-半乳糖苷酶（βgal）的产生减少。它最常见的 导致2至4岁儿童死亡。最近，我们的实验室已经创造了纳米粒子囊泡， 称为聚合物囊泡，能够封装βgal并将其递送至受GM 1影响的细胞的溶酶体，其中 递送的酶保持其活性。GM 1神经节苷脂沉积症猫模型的初步数据显示， 在表面添加载脂蛋白后，聚合物囊泡将活性βgal转运穿过血脑屏障， 前肢静脉注射后48小时。这种治疗方法，名为纳米粒子分布IV ERT（NanoDIVERT）可能会将ERT扩展到中枢神经系统，这不仅会影响 GM 1神经节苷脂沉积症以及其他孤儿神经性LSD。为了进一步测试纳米颗粒的适用性- 介导的IV ERT方法，我们将优化体内性能。具体而言，我们的目标是增加交付， 大脑，并确定最合适的剂量治疗效果。我们的目标是， NanoDIVERT在GM 1神经节苷脂沉积症小鼠模型中的应用，用于在扩大规模前在更多动物中进行试验 到大型动物模型。这些研究的结果可能有助于开发临床相关的ERT GM 1神经节苷脂沉积症和其他神经病性LSD的首次治疗。

PROJECT ABSTRACT Enzyme replacement therapy (ERT) has been successful in ameliorating symptoms of patients with non- neuropathic lysosomal storage disorders (LSDs), making it a viable therapeutic approach for these rare, orphan genetic diseases. Essentially, patients receive intravenous (IV) infusions of endogenous enzymes that are either present at low concentration, missing entirely, or misfolded, and therefore dysfunctional due to their genetic disease. Despite its promise in the clinic, ERT cannot be used to treat 50-70% of LSDs with central nervous system manifestation due to the blood-brain barrier (BBB) which prevents the passage of recombinant enzymes from the blood into the brain. One of these diseases and the focus of this proposal, GM1 gangliosidosis, arises from variants in GLB1 that leads to decreased production of lysosomal β-galactosidase (βgal). Its most common form results in mortality between the ages of 2 and 4. Recently, our laboratory has created nanoparticle vesicles, called polymersomes, capable of encapsulating and delivering βgal to lysosomes of GM1-affected cells, where the delivered enzyme maintains its activity. Preliminary data in a feline model of GM1 gangliosidosis shows that with the addition of an apolipoprotein on the surface, polymersomes transport active βgal across the BBB within 48 hours after an intravenous forelimb injection. This approach to treatment, titled nanoparticle distributed IV ERT (NanoDIVERT), can potentially extend ERT into the central nervous system, which could impact not only GM1 gangliosidosis but also other orphan neuropathic LSDs. To further test the applicability of the nanoparticle- mediated approach to IV ERT, we will optimize in vivo performance. Specifically, we aim to increase delivery to the brain and determine the most appropriate dosing for therapeutic effects. We aim to initially optimize NanoDIVERT in a murine model of GM1 gangliosidosis, for testing in greater animal numbers, before scaling up to large animal models. The outcome of these studies could enable the development of a clinically relevant ERT for GM1 gangliosidosis and other neuropathic LSDs for the first time.