Phenotypic effects of brain-directed enzyme therapy for Sanfilippo B syndrome

脑定向酶疗法对 Sanfilippo B 综合征的表型影响

基本信息

批准号：
9000182
负责人：
PATRICIA I DICKSON
金额：
$ 31.03万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9000182
关键词：
Address Adult Affect Behavioral Binding Binding Sites Brain Canis familiaris Cell Therapy Cells Child Chimeric Proteins Circadian Rhythms Clinical Cognitive Data Destinations Deterioration Development Disease Enzymes FDA approved Genes Glucosaminidase Glycosaminoglycans Health Human Hypothalamic structure IGF Type 2 Receptor Impairment In Vitro Injection of therapeutic agent Insulin-Like Growth Factor II Intraventricular Lead Lysosomal Storage Diseases Lysosomes Mannose Marketing Mediating Modeling Mucopolysaccharidoses Mus N acetylglucosaminidase Neurologic Organ Pathology Patients Peptide Fragments Peripheral Phenotype Phosphorylation Process Production Property Proteins Quality of life Recombinants Research Site Sleep Sleep disturbances Son Staging Stem cells Symptoms Syndrome System Therapeutic Time Visceromegaly Visual impairment behavior test enzyme deficiency enzyme replacement therapy enzyme therapy gene therapy hearing impairment improved in vivo lateral ventricle man mannose 6 phosphate mouse model neurobehavior neurobehavioral neuropathology novel therapeutics pre-clinical receptor receptor binding reduce symptoms scavenger receptor success therapeutic enzyme trafficking treatment effect uptake

项目摘要

DESCRIPTION (provided by applicant): Sanfilippo B syndrome is a devastating lysosomal storage disorder due to deficiency of the enzyme alpha-N- acetylglucosaminidase (NAGLU). Most therapeutic approaches that have been used or proposed for the lysosomal storage diseases that are due to missing enzymes involve replacing that enzyme into the deficient host in some way- either using wild-type donor stem cells (which provide the missing enzyme), gene therapy to deliver the gene that encodes the enzyme, or by recombinant enzyme administration. All of these depend on the special property of lysosomal enzymes that is made possible by the mannose 6-phosphate receptor system: lysosomal enzymes can be secreted by a cell, taken up by another cell via mannose 6-phosphate receptors, and shuttled to lysosomes where they can act to reduce stored substrate. Unfortunately for people affected with Sanfilippo B syndrome, NAGLU does not contain sufficient mannose 6-phosphate when expressed recombinantly, so that cellular uptake and lysosomal targeting never take place. We have generated a fusion construct of NAGLU and a portion of insulin-like growth factor 2 (IGF2). The natural scavenger receptor for IGF2 is the mannose 6-phosphate receptor (though it binds at a different site than does mannose 6- phosphate). Our preliminary in vitro and in vivo data show that recombinant human NAGLU-IGF2 is active, enters cells, and can reduce lysosomal storage with high efficiency. The next step, which this proposal seeks to address, is to determine whether recombinant human NAGLU-IGF2 will improve the Sanfilippo B phenotype, which is one of progressive cognitive deterioration. In this project, we propose to study this potential new therapy in vivo, to determine whether it improves neurobehavior, physical disease, and survival. The results will tell us whether recombinant NAGLU-IGF2 can serve as effective enzyme therapy for this devastating disease. Results may also have implications for gene and cell therapy approaches for Sanfilippo B, which might be made more effective with the use of IGF2-mediated lysosomal targeting.

描述（由适用提供）：Sanfilippo B综合征是由于酶Alpha-N-乙酰基葡萄糖酰胺酶（Naglu）的缺乏而导致的溶酶体储存障碍。 Most therapeutic approaches that have been used or proposed for the lysosomal storage diseases that are due to missing enzymes involve replacing that enzyme into the deficient host in some way- either using wild-type donor stem cells (which provide the missing enzyme), gene therapy to deliver the gene that encodes the enzyme, or by recombinant enzyme administration.所有这些都取决于糖体酶的特殊特性，而溶酶体酶是由6-磷酸甘露糖体受体系统实现的：溶酶体酶可以由一个细胞分泌，通过另一个细胞通过6-磷酸酯受体接收，并穿梭为溶酶体，以减少储存储存的亚糖体。不幸的是，对于患有Sanfilippo B综合征的人来说，Naglu重组表达时不含足够的6-磷酸甘露糖，因此细胞摄取和溶酶体靶向永远不会发生。我们已经生成了Naglu的融合构建体和一部分胰岛素样生长因子2（IGF2）。 IGF2的天然清道夫受体是甘露糖的6-磷酸受体（尽管它在与6-磷酸甘露糖的位点结合）。我们的初步体外和体内数据表明，重组人Naglu-igf2是活跃的，进入细胞，可以以高效率减少溶酶体储存。该提案寻求解决的下一步是确定重组人Naglu-igf2是否会改善Sanfilippo B表型，这是渐进的认知确定之一。在这个项目中，我们建议研究这种潜在的新疗法，以确定它是否改善了神经行为，身体疾病和生存。结果将告诉我们重组Naglu-IgF2是否可以作为这种毁灭性疾病的有效酶治疗。结果也可能对Sanfilippo B的基因和细胞疗法有影响，Sanfilippo B可能会在使用IGF2介导的溶酶体靶向方面更有效。