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Metachromatic Leukodystrophy Enzyme Drug Development

异染性脑白质营养不良酶药物开发

基本信息

批准号：
8390170
负责人：
Ka-Wai Hui
金额：
$ 15.66万
依托单位：
ARMAGEN TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8390170
关键词：
Address Adolescent Adult Affinity Age Animal Testing Animals Arylsulfatases Binding Biological Assay Bioreactors Blindness Blood Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Cell Culture Techniques Cell Line Cell membrane Cells Cessation of life Chemicals Child Childhood Chimeric Proteins Chinese Hamster Chinese Hamster Ovary Cell Chronic Clinical Trials Cloning Coma Confocal Microscopy Convulsions Deglutition Dementia Developmental Delay Disorders Disease Dose Drug Kinetics Engineering Enzymes Evaluation Feasibility Studies Fibroblasts Future Genes Hereditary Disease Human Human Engineering Immunoglobulin G In Vitro Inherited Insulin Receptor Label Macaca mulatta Medical Mental Retardation Metachromatic Leukodystrophy Methodology Methods Modeling Monoclonal Antibodies Muscle Muscle Rigidity Mutation Nerve Degeneration Neuraxis Neurons Organ Ovary Paralysed Penetration Peptide Receptor Peptide Signal Sequences Peripheral Pharmaceutical Preparations Phase Plasma Primates Property Propionates Proteins Radio Recombinant Fusion Proteins Recombinants Research Rodent Scientist Small Business Innovation Research Grant Spinal Cord Symptoms Time Toxic effect Triage Work base brain cell capillary disease-causing mutation drug development enzyme activity enzyme replacement therapy human INSR protein in vivo infancy molecular trojan horse peptidomimetics phase 1 study phase 2 study protein structure response uptake wasting

项目摘要

DESCRIPTION (provided by applicant): Metachromatic leukodystrophy (MLD) is an genetic disease caused by mutations in the gene encoding the lysosomal enzyme, arylsulfatase A (ASA). Symptoms including neurodegeneration and mental retardation appear during infancy or childhood; and early death can occur due to organ damage in the brain. Enzyme replacement therapy (ERT) cannot treat the brain, since recombinant ASA does not cross the blood-brain barrier (BBB). Accordingly, clinical trials of children with MLD and recombinant ASA have been abandoned. The present work will re-engineer human ASA to enable transport across the BBB using a molecular Trojan horse technology. A molecular Trojan horse is a genetically engineered peptidomimetic monoclonal antibody (MAb) against an endogenous BBB peptide receptor, such as the human insulin receptor (HIR). The human ASA is fused to the heavy chain of the HIRMAb to create a new chemical entity, called the HIRMAb-ASA fusion protein. Feasibility studies with the HIRMAb-ASA fusion protein were enabled following the cloning of a high producing, stably transfected host cell line. The HIRMAb-ASA fusion protein retains high ASA enzyme activity and high binding to the HIR. This phase I SBIR work will further validate the pharmacologic activity of the HIRMAb-ASA fusion protein in MLD fibroblasts, using ASA enzyme activity assays and confocal microscopy. The HIRMAb-ASA fusion protein penetration of the BBB in vivo will be confirmed in the Rhesus monkey. This work provides the rationale for future phase II studies that provide the bridge to subsequent GMP/GLP work that supports an IND for treatment of MLD with the HIRMAb-ASA fusion protein. PUBLIC HEALTH RELEVANCE: Metachromatic leukodystrophy (MLD) is an genetic disease caused by mutations in the gene encoding the lysosomal enzyme, arylsulfatase A (ASA). Enzyme replacement therapy cannot treat the brain, since recombinant ASA does not cross the blood-brain barrier. The present work will re- engineer human ASA to enable transport across the BBB using a molecular Trojan horse technology.

描述（由申请人提供）：异染性脑白质营养不良（MLD）是一种由编码溶酶体酶芳基硫酸酯酶A（阿萨）的基因突变引起的遗传性疾病。包括神经变性和智力迟钝在内的症状出现在婴儿期或儿童期;由于大脑器官损伤，可能会发生早逝。酶替代疗法（ERT）不能治疗大脑，因为重组阿萨不能穿过血脑屏障（BBB）。因此，MLD和重组阿萨儿童的临床试验已被放弃。目前的工作将重新设计人类阿萨，使运输通过BBB使用分子特洛伊木马技术。分子特洛伊木马是针对内源性BBB肽受体（如人胰岛素受体（HIR））的基因工程化的拟肽单克隆抗体（MAb）。人阿萨与HIRMAb的重链融合，形成一种新的化学实体，称为HIRMAb-ASA融合蛋白。在克隆高产、稳定转染的宿主细胞系后，能够进行HIRMAb-ASA融合蛋白的可行性研究。HIRMAb-ASA融合蛋白保留高阿萨酶活性和与HIR的高结合。该I期SBIR工作将使用阿萨酶活性测定和共聚焦显微镜进一步验证HIRMAb-ASA融合蛋白在MLD成纤维细胞中的药理学活性。将在恒河猴中证实BBB的体内HIRMAb-ASA融合蛋白渗透。这项工作为未来的II期研究提供了依据，这些研究为后续的GMP/GLP工作提供了桥梁，支持用HIRMAb-ASA融合蛋白治疗MLD的IND。公共卫生相关性：异染性脑白质营养不良（MLD）是一种由编码溶酶体酶芳基硫酸酯酶A（阿萨）的基因突变引起的遗传性疾病。酶替代疗法不能治疗大脑，因为重组阿萨不能穿过血脑屏障。目前的工作将重新设计人类阿萨，使运输通过血脑屏障使用分子特洛伊木马技术。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pharmacokinetics and brain uptake in the rhesus monkey of a fusion protein of arylsulfatase a and a monoclonal antibody against the human insulin receptor.

DOI：
10.1002/bit.24795
发表时间：
2013-05
期刊：
BIOTECHNOLOGY AND BIOENGINEERING
影响因子：
3.8
作者：
Boado, Ruben J.;Lu, Jeff Zhiqiang;Hui, Eric K. -W.;Sumbria, Rachita K.;Pardridge, William M.
通讯作者：
Pardridge, William M.