Nanoparticle Distributed Intravenous Enzyme Replacement Therapy (NanoDIVERT)

纳米颗粒分布式静脉酶替代疗法（NanoDIVERT）

基本信息

批准号：
10723846
负责人：
Jessica Marie Larsen
金额：
$ 40.46万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723846
关键词：
Adjuvant Affect Age Animal Model Animals Apolipoprotein E Apolipoproteins Area Autopsy Biodistribution Blood Blood - brain barrier anatomy Brain Brain Diseases COVID-19 vaccine Cells Central Nervous System Clinic Clinical Clinical Trials Data Development Disease Dose Dyes Encapsulated Enzymes Family Family Felidae Forelimb Future GLB1 gene Gangliosidosis GM1 Genetic Diseases Goals Half-Life Hour Human Inflammation Injections Intravenous Intravenous infusion procedures Laboratories Low-Density Lipoproteins Lysosomal Storage Diseases Lysosomes Marketing Mediating Modeling Monitor Mus Neurologic Neuropathy Orphan Outcome Study Patients Performance Production Proteins Recombinants Regimen Severity of illness Specificity Spinal Cord Surface Symptoms System Testing Therapeutic Therapeutic Effect Time Tissues Treatment Efficacy Variant Vesicle adeno-associated viral vector appropriate dose beta-Galactosidase clinically relevant common symptom enzyme activity enzyme replacement therapy flexibility gene therapy improved in vivo in vivo imaging system infancy intravenous injection mortality mouse model nanoparticle near infrared dye neural neurotoxicity prevent receptor reduce symptoms scale up success vector

项目摘要

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.

项目摘要酶替代疗法 (ERT) 已成功改善非神经性溶酶体贮积症 (LSD)，使其成为治疗这些罕见孤儿病的可行方法本质上，患者接受静脉（IV）输注内源性酶，这些酶要么是遗传性疾病。浓度低、完全缺失或错误折叠，因此由于其遗传原因而功能失调尽管 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。由于血脑屏障（BBB）阻止重组酶通过而导致的系统表现这些疾病之一和本提案的重点是 GM1 神经节苷脂沉积症。 GLB1 变异导致溶酶体 β-半乳糖苷酶 (βgal) 产量减少，这是最常见的。形式导致 2 至 4 岁之间的死亡率。最近，我们的实验室创建了纳米颗粒囊泡，称为聚合物囊泡，能够封装 βgal 并将其递送至 GM1 影响细胞的溶酶体，其中递送的酶在 GM1 神经节苷脂沉积症猫科动物模型中保持其活性。通过在表面添加载脂蛋白，聚合物囊泡可将活性 βgal 转运穿过 BBB 前肢静脉注射后 48 小时，这种治疗方法被称为纳米颗粒分布式静脉注射。 ERT (NanoDIVERT) 可以将 ERT 扩展到中枢神经系统，这不仅会影响 GM1 神经节苷脂沉积症以及其他孤儿神经性 LSD 进一步测试纳米颗粒的适用性。 IV ERT 介导方法，我们将优化体内性能，具体而言，我们的目标是增加递送。我们的目标是初步优化大脑并确定最合适的治疗剂量。 NanoDIVERT 在 GM1 神经节苷脂沉积症小鼠模型中进行，用于在扩大规模之前对更多动物进行测试这些研究的结果可以促进临床相关 ERT 的开发。首次用于治疗 GM1 神经节苷脂沉积症和其他神经性 LSD。