Targeted enzyme delivery systems for treatment of orphan niemann-pick disease

用于治疗孤儿尼曼皮克病的靶向酶递送系统

基本信息

批准号：
7267910
负责人：
SILVIA MURO
金额：
$ 19.12万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7267910
关键词：
Targeted enzyme delivery systems treatment

项目摘要

DESCRIPTION (provided by applicant): Type A and B Niemann-Pick disease (NPD) is a chronic lysosomal storage disorder (LSD) due to a genetic deficiency of acid sphingomyelinase (ASM), which causes aberrant accumulation of sphingomyelin and cholesterol. Storage in the reticulo-endothelial system (RES; sphingomyelin scavengers) and vascular endothelial cells (ECs; a major ASM source) causes hepatosplenomegaly, vascular dystonia, thrombosis, atherosclerosis, and pulmonary inflammation. As a consequence, NPD results in high morbidity and premature mortality in patients. Enzyme replacement therapy (ERT) for NPD depends on receptors that recognize ASM sugar residues and induce clathrin-mediated uptake. Suboptimal glycosylation of recombinant ASM and altered clathrin-dependent endocytosis in NPD cells limit enzyme delivery. This justifies the design of alternative strategies, yet development of novel NPD therapies is hampered due to low incidence of this orphan disease. We hypothesize that effective ERT requires means bypassing glycosylation and clathrin pathways and propose an alternative strategy: targeting Intercellular Adhesion Molecule (ICAM) -1, a glycoprotein expressed on diverse cell types (predominantly ECs and RES), up-regulated and functionally involved in NPD pathology. We showed that prototype ICAM-1-targeted nanocarriers (polystyrene beads coated with anti-ICAM and ASM) are internalized by cells via CAM-mediated endocytosis (a non-classical pathway that is not affected in NPD) and enhance ASM targeting in mice and lysosomal delivery in cells. Evaluation of the therapeutic utility of this strategy will require recurrent administrations, compelling substitution of immunogenic antibody and non-degradable beads by viable compounds. We propose to explore ASM delivery by biocompatible PLGA nanocarriers targeted by anti-ICAM single-chain Fv (scFv). We hypothesize that this system will: a) deliver ASM to NPD organs and cells; b) address ASM to lysosomes; and c) restore ASM activity. We will test these hypotheses in the following Aims: 1-Characterize targeting of ICAM-1-addressed ASM; 2-Define lysosomal delivery of ICAM-1-targeted ASM; and 3-Evaluate the recovery of ASM activity delivered by ICAM-1-targeted system, in both cells and animal models. This study will provide a biocompatible system suitable for future studies on the safety and therapeutic utility of ICAM-1-targeted NPD ERT. The clinical benefits of this strategy may be extended to other LSDs.

描述（由申请人提供）：A型和B型尼曼 - 踢作疾病（NPD）是一种慢性溶酶体储存障碍（LSD），这是由于酸性鞘磷脂酶（ASM）的遗传缺乏，导致鞘磷脂和胆固醇的异常积累。在网状内皮系统（RES；鞘磷脂清除剂）和血管内皮细胞（ECS；主要的ASM来源）中存储会导致肝肿大肿大，血管肌张力障碍，血栓形成，动脉粥样硬化和肺部炎症。结果，NPD导致患者的发病率高和过早死亡。 NPD的酶替代疗法（ERT）取决于识别ASM糖残基并诱导网格蛋白介导的摄取的受体。 NPD细胞中重组ASM和网格蛋白依赖性内吞作用改变的糖基化降低了酶限制酶的递送。这证明了替代策略的设计合理，但由于这种孤儿疾病的发生率低，新型NPD疗法的发展受到阻碍。我们假设有效的ERT需要意味着绕过糖基化和网格蛋白途径，并提出了一种替代策略：靶向细胞间粘附分子（ICAM）-1，一种在多种细胞类型（主要是ECS和RESS）上表达的糖蛋白（主要是ECS和RESS），涉及NPD病理学。我们表明，原型ICAM-1靶向的纳米载体（涂有抗ICAM和ASM的聚苯乙烯珠）是通过CAM介导的内吞作用（一种不影响NPD影响的非经典途径）的细胞内化的，并增强细胞中小鼠和溶酶体递送的ASM靶向。评估该策略的治疗效用将需要复发，以可行的化合物替代免疫原性抗体和不可降解的珠子。我们建议探索由抗ICAM单链FV（SCFV）靶向的生物相容性PLGA纳米载体的ASM传递。我们假设该系统将：a）向NPD器官和细胞传递ASM； b）ASM地址溶酶体； c）还原ASM活动。我们将在以下目的中检验这些假设：1特征靶向ICAM-1添加的ASM； ICAM-1-1靶向ASM的2级溶酶体递送； 3评估通过ICAM-1靶向系统，在细胞和动物模型中恢复ASM活性。这项研究将提供一个适用于ICAM-1靶向NPD ERT的安全性和治疗效用的生物相容性系统。该策略的临床益处可以扩展到其他LSD。