Nanoparticle Distributed Intravenous Enzyme Replacement Therapy (NanoDIVERT)

项目摘要 酶替代疗法(ERT)已成功地改善非霍奇金淋巴瘤患者的症状。 神经病理性溶酶体储存障碍(LSD)，使其成为这些罕见的孤儿的可行治疗方法 遗传病。基本上，患者接受静脉(IV)输注内源性酶，这些酶可以是 以低浓度存在、完全缺失或错误折叠，因此由于它们的基因而功能失调 疾病。尽管ERT在临床上很有希望，但它不能用于治疗50%-70%的LSD合并中枢神经系统疾病 由于血脑屏障(BBB)阻止重组酶通过而导致的系统表现 从血液进入大脑。这些疾病中的一种，也是本提案的焦点，GM1神经节苷脂沉积症 导致溶酶体β-半乳糖苷酶(βGAL)产生减少的GLB1变异体。它是最常见的 形式会导致2到4岁的儿童死亡。最近，我们的实验室创造了纳米颗粒囊泡， 称为聚合体，能够包裹βGal并将其运送到受GM1影响的细胞的溶酶体中，其中 交付的酶保持其活性。GM1神经节苷脂沉积症猫科动物模型的初步数据显示 随着载脂蛋白在表面的增加，多聚体将活性β半乳糖跨血脑屏障运送到 静脉注射前肢后48小时。这种治疗方法被称为纳米粒子分布IV ERT(NanoDIVERT)，可能会将ERT扩展到中枢神经系统，这不仅会影响 GM1神经节苷脂沉着症，也是其他孤儿神经性LSD。为了进一步测试纳米颗粒的适用性- 将介导性方法应用于IVERT，我们将优化体内性能。具体地说，我们的目标是将交付增加到 并确定最合适的治疗效果剂量。我们的目标是初步优化 用于GM1神经节苷脂增多症小鼠模型的NanoDIVERT，用于在扩大规模之前在更多动物中进行测试 到大型动物模型。这些研究的结果可能使临床相关ERT的发展成为可能 首次用于GM1神经节苷脂沉着症和其他神经性LSD。

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.