Iduronidase Replacement Therapy of the Brain in Hurler's Syndrome

描述（由申请人提供）：摘要有超过40种溶酶体贮积症，这些疾病中的大多数对中枢神经系统（CNS）产生不利影响。主要的治疗方法是酶替代疗法（ERT）。然而，ERT对大脑无效，因为酶不能穿过体内形成血脑屏障（BBB）的脑毛细血管壁。如果不治疗中枢神经系统，年轻患者注定要进行性神经变性和死亡。未来治疗这些疾病的限制因素是酶穿过BBB的运输。通过直接注射到大脑中来绕过BBB是无效的，因为只有一小部分大脑用经颅递送系统治疗。相反，几乎所有的脑细胞都可以用经血管递送系统治疗，该系统使酶能够在静脉内施用后穿过BBB。大分子如酶的BBB递送的新方法是分子特洛伊木马技术。用基因工程产生双功能融合蛋白，其中缺失的重组酶与BBB分子特洛伊木马融合。后者是一种基因工程蛋白质，能够通过受体介导的内源性BBB肽转运系统的胞转作用穿过人BBB。临床前研究表明，分子量> 100，000道尔顿的大酶可以在附着到BBB受体特异性特洛伊木马后通过运输穿过BBB递送到大脑。目前的工作将产生一种新的融合基因编码的人艾杜糖醛酸酶和基因工程分子特洛伊木马，这将允许相应的融合蛋白，AGT-181的生产。这种新的融合蛋白将成为治疗Hurler综合征的新方法。这项工作的目的是生产生物反应器产生的AGT-181，执行这种新药的GLP药理学-毒理学，检查AGT-181的组织交叉反应性，并准备和向FDA提交用于治疗Hurler综合征大脑的IND。 公共卫生相关性：溶酶体贮积症是一种严重的先天性代谢缺陷，在约40种溶酶体贮积症中，约75%累及大脑。主要的治疗方法是酶替代疗法（ERT）。然而，ERT在大脑中无效，因为酶不能穿过血脑屏障（BBB）。本工作将产生一种新的重组融合蛋白，其能够（a）结合人BB B受体以触发转运到脑中，并且（B）保留高溶酶体酶活性。这种被命名为AGT-181的新药将成为治疗Hurler综合征的新药物。

DESCRIPTION (provided by applicant): Abstract There are over 40 lysosomal storage disorders, and most of these diseases affect adversely the central nervous system (CNS). The mainstay of treatment is enzyme replacement therapy (ERT). However, ERT is not effective for the brain, because the enzymes do not cross the brain capillary wall, which forms the blood-brain barrier (BBB) in vivo. Without treatment of the CNS, the young patients are destined to progressive neurodegeneration and death. The limiting factor in the future treatment of these diseases is the transport of the enzyme across the BBB. Bypass of the BBB with direct injection into the brain is not effective, because only a small part of the brain is treated with a trans-cranial delivery system. Conversely, virtually all cells of the brain can be treated with a trans-vascular delivery system that enables the enzyme to cross the BBB following intravenous administration. A new approach to the BBB delivery of large molecules such as enzymes is the molecular Trojan horse technology. A bi-functional fusion protein is produced with genetic engineering, wherein the missing recombinant enzyme is fused to a BBB molecular Trojan horse. The latter is a genetically engineered protein that is able to cross the human BBB by receptor- mediated transcytosis on endogenous BBB peptide transport systems. Pre-clinical studies show that a large enzyme with a molecular weight >100,000 Daltons, can be delivered to brain via transport across the BBB, following attachment to a BBB receptor-specific Trojan horse. The present work will produce a novel fusion gene encoding human iduronidase and a genetically engineered molecular Trojan horse, which will allow the production of the corresponding fusion protein, AGT-181. This new fusion protein will be a new treatment of the brain in Hurler's syndrome. The aims of this work are to manufacture bioreactor-generated AGT-181, perform the GLP pharmacology-toxicology of this new drug, examine the tissue cross reactivity of AGT-181, and to prepare and file an IND to the FDA for the treatment of the brain in Hurler's syndrome. PUBLIC HEALTH RELEVANCE: Project Narrative Lysosomal storage disorders are serious inborn errors of metabolism, and about 75% of the ~40 lysosomal storage disorders affect the brain. The mainstay of treatment is Enzyme Replacement Therapy (ERT). However, ERT is ineffective in the brain, because the enzymes do not cross the blood-brain barrier (BBB). The present work will produce a novel recombinant fusion protein that is able to both (a) bind a human BBB receptor to trigger transport into the brain, and (b) retain high lysosomal enzyme activity. This novel drug, designated AGT-181, will be new treatment for the brain in Hurler's syndrome.