Intranasal Sulfamidase Delivery to the Brain

鼻内磺酰胺酶输送至大脑

• 批准号: 8979416
• 负责人: Charles Alexander Glass
• 金额: $ 23.71万
• 依托单位: TEGA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8979416
• 关键词: Abbreviations; Acute; Antibody Formation; Behavioral; Biodistribution; Biological Markers; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Part; CNS degeneration; Carbohydrates; Cell membrane; Cell surface; Cells; Cerebrospinal Fluid; Chondroitin; Complex; Deposition; Dermatan Sulfate; Development; Disease; Dose; Drug Kinetics; Endocytosis; Enzymes; Excretory function; GAG Gene; Glycosaminoglycan Degradation Pathway; Glycosaminoglycans; Glycosides; Glycosphingolipids; Goals; Grant; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hepatic; Histology; Human; Hyaluronan; IGF Type 2 Receptor; Inflammation; Inflammatory; Injection of therapeutic agent; Inorganic Sulfates; Intranasal Administration; Intravenous; L-Iduronidase; Life; Long-Term Effects; Lysosomes; Measurement; Measures; Mental Retardation; Methods; Modeling; Molecular Weight; Mucopolysaccharidoses; Mucopolysaccharidosis I S; Mus; Mutation; Neomycin; Neuraxis; Nose; Online Mendelian Inheritance In Man; Pathologic; Patients; Penetration; Phase; Process; Production; Proteins; Regimen; Route; Safety; Spinal Cord; Structural Genes; Symptoms; System; Testing; Therapeutic; Time; Tissues; Toxic effect; Unspecified or Sulfate Ion Sulfates; Urine; base; cytokine; drug development; enzyme activity; enzyme replacement therapy; in vivo; inflammatory marker; intravenous injection; irritation; mannose 6 phosphate; mouse model; neuropathology; novel; pre-clinical; programs; public health relevance; sugar

 DESCRIPTION (provided by applicant): MPS IIIA (Sanfilippo A) is a disease in which a key enzyme is missing in cells resulting in the accumulation of a type of complex sugar called a glycosaminoglycan in various tissues. 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. Unfortunately, enzyme replacement does not resolve complications of the disease in the central nervous system. This proposal focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS IIIA, a disease with no current therapeutic options. We show that we can deliver the missing enzyme to cells derived from MPS IIIA patients and that intravenous injection of modified enzyme reduces storage of glycosaminoglycans in a mouse model of MPS IIIA (Sgsh-/-). Furthermore, intranasal administration of modified enzyme demonstrated high levels of delivery to the brain and reduction of pathological glycosaminoglycans. The purpose of this grant is to optimize the transfer of enzyme into the central nervous system in the MPS IIIA mouse model and then assess the efficacy and safety in a long-term (6-month) study. The results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans.

 描述（由申请人提供）：MPS IIIA（Sanfilippo A）是一种细胞中缺少关键酶，导致一种称为糖胺聚糖的复合糖在各种组织中积累的疾病，是治疗相关类型的主要方法。酶替代治疗涉及通过注射到循环中来替代缺失的酶，但不幸的是，酶替代并不能解决中枢神经系统疾病的并发症。进行酶替代疗法的方法及其在 MPS IIIA 中的应用，这是一种目前没有治疗选择的疾病，我们表明我们可以将缺失的酶传递给来自 MPS IIIA 患者的细胞，并且静脉注射修饰酶可减少糖胺聚糖在细胞中的储存。 MPS IIIA (Sgsh-/-) 小鼠模型此外，修饰酶的鼻内给药显示出高水平的递送至大脑并减少了病理性糖胺聚糖。这项资助的目的是优化转移。在 MPS IIIA 小鼠模型中将酶引入中枢神经系统，然后在长期（6 个月）研究中评估其功效和安全性，结果将为该疾病的新型治疗提供所需的临床前信息。人类。