Title: Intracerebroventricular sulfamidase delivery to the Brain

标题：脑室内磺酰胺酶递送至大脑

• 批准号: 10010624
• 负责人: Jillian R Brown
• 金额: $ 25.82万
• 依托单位: TEGA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010624
• 关键词: Animals; Biochemical; Biodistribution; Biological Markers; Blood - brain barrier anatomy; Blood Circulation; Brain; Bypass; CNS degeneration; Carbohydrates; Cell membrane; Cell surface; Cells; Cerebrospinal Fluid; Chondroitin; Complex; Deposition; Dermatan Sulfate; Development; Disease; Dose; Drug Kinetics; Effectiveness; Endocytosis; Enzymes; Excretory function; Feasibility Studies; GAG Gene; Glycosaminoglycan Degradation Pathway; Glycosaminoglycans; Glycosides; Glycosphingolipids; Goals; Grant; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hepatic; Histologic; Human; Hyaluronan; Inflammation; Injections; Intranasal Administration; Intravenous; L-Iduronidase; Lysosomal Storage Diseases; Lysosomes; Measures; Mental Retardation; Methods; Modeling; Molecular Weight; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis I S; Mus; Mutation; Nature; Neomycin; Nerve Degeneration; Neuraxis; Neurologic Symptoms; Online Mendelian Inheritance In Man; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Proteins; Route; Safety; Spinal Cord; Structural Genes; Sulfate; Symptoms; System; Testing; Time; Tissues; Toxic effect; Urine; acute toxicity; base; behavioral study; blood-brain barrier penetration; brain volume; cell injury; enzyme replacement therapy; in vivo; intravenous injection; molecular transporter; mouse model; novel; pre-clinical; prevent; sugar; translation to humans

PROJECT SUMMARY MPS IIIA is lysosomal storage disease; a disease in which a key enzyme, sulfamidase (SGSH) is missing in cells, resulting in the toxic accumulation of complex sugars called glycosaminoglycans, principally in the central nervous system (CNS). A primary approach for treating related types of disorders involves replacement of the missing enzyme by injection into the circulation. Enzyme replacement therapy resolves many aspects of the disease but unfortunately it does not resolve complications of the disease in the CNS. This proposal focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS IIIA, a disease with severe neurodegenerative symptoms but with very limited current therapies due to poor transport across the blood-brain barrier. We have tested our approach on a similar disease, MPSI; which is missing a different key enzyme called iduronidase (IDUA). Using iduronidase (IDUA) conjugated to guanidinoneomycin (GNeo), a molecular transporter, we showed that we can deliver the missing enzyme to cells derived from MPS I patients and that intranasal administration of small amounts of the conjugated enzyme were sufficient to reduce pathological glycosaminoglycans in the brain. The purpose of this grant is conjugate SGSH with GNeo (GNeo-SGSH) and assess the effectiveness of enzyme replacement therapy delivered directly to the central nervous system in the MPS IIIA mouse model using intracerebroventricular administration. Dose-dependent biodistribution of GNeo-SGSH and effects on biochemical and histological pathology will be evaluated. Efficacy and safety will be assessed in single dose and 2-week dosing studies. The results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans.

项目摘要 MPS IIIA是溶酶体储存疾病；其中缺少关键酶，磺酰酶（SGSH）的疾病 细胞，导致称为糖胺聚糖的复杂糖的有毒积累，主要在中央 神经系统（CNS）。治疗相关疾病类型的主要方法涉及替换 通过注射到循环中缺少酶。酶替代疗法解决了 疾病，但不幸的是，它不能解决中枢神经系统中该疾病的并发症。该提案重点是 关于开发一种新的方法来执行酶替代疗法及其在MPS IIIA的应用 患有严重神经退行性症状的疾病，但由于运输差而导致的当前疗法非常有限 穿过血脑屏障。我们已经测试了类似疾病MPSI的方法；缺少一个 不同的键酶称为iduronidase（idua）。使用偶像蛋白替酶（IDUA）结合到瓜尼替霉素 （称者），一种分子转运蛋白，我们表明我们可以将缺失的酶传递到来自MPS的细胞 I患者和鼻内给药少量的共轭酶足以足以 减少大脑中的病理糖胺聚糖。这笔赠款的目的是与媒体共轭sgsh （称呼SGSH）并评估直接递送到中心的酶替代疗法的有效性 MPS IIIA小鼠模型中使用脑室内给药的神经系统。剂量依赖性 将评估片麻岩的生物分布以及对生化和组织理论病理学的影响。功效 和安全性将在单剂量和2周的剂量研究中进行评估。结果将提供临床前 需要进行对人类疾病的新对待所需的信息。