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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：
9234075
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/9234075
关键词：
Address Adult Affect Alpha Cell Behavioral Binding Binding Sites Brain Canis familiaris Cell Therapy Cells Child Chimeric Proteins Circadian Rhythms Cognitive Data Destinations Deterioration Development Disease Enzymes FDA approved Genes Glycosaminoglycans Human Hypothalamic structure IGF Type 2 Receptor IGF2R gene Impairment In Vitro Injection of therapeutic agent Insulin-Like Growth Factor II Intraventricular Lead Lysosomal Storage Diseases Lysosomes Mannose Manufactured form Mediating Modeling Mucopolysaccharidoses Mus Neurologic Organ Pathology Patients Peptide Fragments Phenotype Phosphorylation Process Production Property Proteins Quality of life Recombinants Research Site Sleep Sleep disturbances Stem cells Symptoms Syndrome System Therapeutic Time Visceromegaly Visual impairment alpha-n-acetylglucosaminidase behavior test clinical development enzyme deficiency enzyme replacement therapy enzyme therapy gene therapy hearing impairment improved in vivo lateral ventricle mannose 6 phosphate mouse model neurobehavior neurobehavioral neuropathology novel therapeutics preclinical development public health relevance 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.