Genetic Therapy for CNS Manifestations in MPS I via BBB-targeted Protein Delivery

通过 BBB 靶向蛋白递送对 MPS I 中的中枢神经系统表现进行基因治疗

基本信息

批准号：
8321014
负责人：
Dao Pan
金额：
$ 32.16万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321014
关键词：
Affect Age Aging Allogenic Alzheimer&apos s Disease Apolipoprotein E Behavior assessment Behavioral Binding Biodistribution Biological Assay Blood - brain barrier anatomy Blood Circulation Blood capillaries Brain Cell Line Cells Central Nervous System Diseases Chimeric Proteins Congenital neurologic anomalies Data Development Diagnostic Endothelium Enzymes Erythrocytes Erythroid Erythroid Cells Evaluation Family Fibroblasts Frequencies GAG Gene Gene Delivery Gene Transfer Goals Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hepatic Hepatocyte Human In Vitro Injection of therapeutic agent Intravenous Knowledge L-Iduronidase Lead Lentivirus Vector Liver Low Density Lipoprotein Receptor Luciferases Lysosomal Storage Diseases Mediating Metabolic Methods Modeling Monitor Mucopolysaccharidosis I Mus Neonatal Neuraxis Neurologic Neurons Organ Pathologic Pathology Patients Peripheral Plasma Plasmids Production Proteins Public Health Red Cell Mass result Route Series Side Spatial Distribution Stroke System Testing Therapeutic Therapeutic Effect Tissues Transgenes Work abstracting base capillary cellular transduction enzyme replacement therapy gene therapy in vivo intravenous injection member nanoparticle nervous system disorder novel strategies novel therapeutic intervention overexpression postnatal preclinical evaluation promoter protein distribution public health relevance receptor receptor mediated endocytosis trafficking transcytosis uptake vector

项目摘要

DESCRIPTION (provided by applicant): Abstract Mucopolysaccharidosis type I (MPS I), resulting from the deficiency of alpha-L- iduronidase (IDUA), is one of the most common lysosomal storage diseases (LSD) affecting the central nervous system (CNS), which cannot be cured by current treatments. We have shown that lentiviral vector (LV)-mediated gene delivery can produce sustained supraphysiological IDUA levels in plasma and may be therapeutic in treating CNS manifestations if the blood-brain barrier (BBB) can be overcome. The utilization of the endogenous receptor-mediated transcytosis system on BBB-forming brain capillary endothelium will enable rapid and wide delivery of neurotherapeutics across the BBB via circulation. The overall goal of the work proposed is to develop a novel therapeutic approach utilizing low-density lipoprotein receptor family (LDLRf)- mediated transcytosis for fusion protein delivery across the BBB via LV-mediated gene transfer in the liver and/or the HSC for the treatment of CNS manifestations in MPS I. We will identify, by in vitro and in vivo evaluation, the optimal LDLRf-binding domain of apoE for most efficient BBB transport while retaining the normal catalytic function and lysosomal enzyme trafficking of fusion IDUA (Specific Aim 1). The spatial and temporal protein distribution profile will be studied in the CNS and peripheral organs, targeting the liver or HSC-derived erythroid cells as depot organ for tissue-specific transgene production in mice with different ages (Specific Aim 2). Preclinical evaluation will be conduced in a murine MPS I model to identify window of CNS treatment by GAG assay for metabolic correction, pathology evaluation for CNS normalization and behavioral assessments for improvement of CNS functional deficits (Specific Aim 3). Taken together, these studies will not only lead to the development of a novel approach for the treatment of neurological diseases, such as in MPS I, with lifelong BBB-targeted protein delivery, but also provide important knowledge of in vivo changes in receptor-mediated BBB transport system with aging or under pathological conditions. PUBLIC HEALTH RELEVANCE: Narrative The blood-brain-barrier has hindered the capability of rapid and wide delivery of neurotherapeutics and diagnostic agents to the central nervous system. The studies described in this application will open the door to novel approaches for the treatment of neurological disorders-from MPS type I to major public health concerns such as stroke and Alzheimer's disease.

描述（由申请人提供）： I型I型（MPS I）的抽象性粘多糖含量是由影响中枢神经系统（CNS）的最常见的溶酶体储存疾病（LSD）引起的，这是最常见的溶酶体储存疾病（LSD）之一，无法通过当前治疗方法治愈。我们已经表明，慢病毒载体（LV）介导的基因递送可以在血浆中产生持续的超生理IDUA水平，如果可以克服血脑屏障（BBB），则可以治疗中枢神经系统表现。内源性受体介导的转胞细胞增多症在BBB形成的脑毛细血管内皮上的利用将通过循环迅速而广泛地传递神经疗法。 The overall goal of the work proposed is to develop a novel therapeutic approach utilizing low-density lipoprotein receptor family (LDLRf)- mediated transcytosis for fusion protein delivery across the BBB via LV-mediated gene transfer in the liver and/or the HSC for the treatment of CNS manifestations in MPS I. We will identify, by in vitro and in vivo evaluation, the optimal LDLRf-binding APOE的域可用于最有效的BBB传输，同时保留融合IDUA的正常催化功能和溶酶体酶运输（特定目标1）。将在中枢神经系统和外围器官中研究空间蛋白分布谱，以不同年龄的小鼠的组织特异性转基因产生的仓库靶向肝脏或HSC衍生的红细胞器官（特定AIM 2）。将在鼠MPS I模型中抑制临床前评估，以通过GAG分析来鉴定CNS治疗的窗口，用于代谢校正，CNS归一化的病理评估以及改善CNS功能缺陷的行为评估（特定目标3）。综上所述，这些研究不仅会导致一种新的方法来治疗神经系统疾病，例如在MPS I中，具有终生的BBB靶向蛋白质递送，而且还提供了有关受体介导的BBB运输系统中体内变化的重要知识，具有老化或病理状况。公共卫生相关性：叙述性血脑屏障阻碍了神经疗法和诊断剂向中枢神经系统快速和广泛输送的能力。本应用中描述的研究将为治疗神经系统疾病的新方法打开大门，从I型MPS对中风和阿尔茨海默氏病等主要公共卫生问题进行治疗。