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）：转交白细胞营养不良（MLD）是由编码溶酶体酶，芳基硫酸蛋白酶A（ASA）的基因突变引起的遗传疾病。在婴儿期或童年时期出现包括神经退行性和智力低下的症状；并且可能由于大脑的器官损伤而发生早期死亡。酶替代疗法（ERT）无法治疗大脑，因为重组ASA不跨越血脑屏障（BBB）。因此，已放弃了MLD和重组ASA儿童的临床试验。目前的工作将重新设计人类ASA，可以使用分子特洛伊木马技术在BBB上运输。分子木马是针对内源性BBB肽受体的基因工程肽单克隆抗体（MAB），例如人类胰岛素受体（HIR）。人类ASA与Hirmab的重链融合在一起，以创建一种新的化学实体，称为Hirmab-ASA融合蛋白。在克隆高产生，稳定转染的宿主细胞系后，对Hirmab-ASA融合蛋白进行了可行性研究。 Hirmab-ASA融合蛋白保留了高ASA酶活性，并且与HIR的结合高。使用ASA酶活性测定和共聚焦显微镜，这一I期SBIR的工作将进一步验证MLD成纤维细胞中Hirmab-ASA融合蛋白的药理活性。 BBB在体内的Hirmab-ASA融合蛋白渗透将在恒河猴中得到证实。这项工作为未来的II期研究提供了理由，该研究为随后的GMP/GLP工作提供了支持，该工作支持IND，用于用Hirmab-ASA融合蛋白治疗MLD。公共卫生相关性：分泌白细胞营养不良（MLD）是一种由编码溶酶体酶，芳基硫酸蛋白酶A（ASA）的基因突变引起的遗传疾病。酶替代疗法无法治疗大脑，因为重组ASA不会越过血脑屏障。目前的工作将使用分子特洛伊木马技术来促进人类ASA启用BBB的运输。

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.