Targeted replacement of defective lysosomal enzymes in the lung and brain

有针对性地替代肺和脑中有缺陷的溶酶体酶

基本信息

批准号：
9898422
负责人：
SILVIA MURO
金额：
$ 40.29万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898422
关键词：
Affect Antibodies Award Blood Brain Cell Adhesion Molecules Cell model Cells Cessation of life Chronic Clathrin Combined Modality Therapy Coupled Disease Dose Encapsulated Endothelium Engineering Enhancers Environment Enzymes Equilibrium Formulation Frequencies Genetic Glycolates Goals Health Health system Hospitals Immune In Vitro Inflammation Inflammatory Infusion procedures Intercellular adhesion molecule 1 Journals Kidney Lead Liposomes Liver Lung Lung diseases Lysosomal Storage Diseases Lysosomes Mechanics Medical Microfluidic Microchips Mission Mus Neurologic Niemann-Pick Diseases Organ Pathology Pathway interactions Patients Penetration Performance Peripheral Phagocytes Phenotype Polymers Proteins Public Health Recombinants Regulation Research Research Personnel Resistance Role Route Signal Transduction Sphingomyelins Spleen Surface Symptoms Testing Therapeutic Time Tissues Translations United States National Institutes of Health acid sphingomyelinase biochemical model biodegradable polymer biomaterial compatibility clinically relevant design dosage editorial effective therapy enzyme activity enzyme deficiency enzyme replacement therapy enzyme substrate enzyme therapy follow-up immune resistance immunoreaction improved innovation intercellular cell adhesion molecule mouse model nanocarrier overexpression parent grant premature receptor side effect success therapeutic enzyme transcytosis uptake

项目摘要

SUMMARY The lysosomal storage (LSDs) disorders comprise ~50 fatal diseases due to genetic lysosomal enzyme deficiency, which affects most tissues and associates to broad inflammatory phenotype. Treatment is by enzyme replacement therapy (ERT), where recombinant enzymes are i.v. infused in hospitals, with high burden to patients and the health system (≥$150,000/patient- year). Still, ERT success is restricted to a few diseases that affect the liver, spleen, and kidneys, since the enzymes access these blood clearance organs. Yet, delivery to tissues separated from the blood by a tight endothelial barrier (mainly the brain, to some extent the lungs) is hindered. An example is that of types A-B NPD, a sphingomyelin storage due to acid sphingomyelinase (ASM) deficiency, which leads to premature death. NPD-A has a strong neurological involvement, not improved by ERT. NPD-B mainly affects the lungs and, although helped by ERT, high and frequent dosage causes immune reactions and resistance, along with other side effects. Our original award focused on targeting recombinant ASM to ICAM-1, a protein overexpressed in inflammation and associated to a new route of transport across the endothelium and into lysosomes of tissue cells. Through the previous period we successfully achieved our goals and improved: brain and lung targeting, transport across the endothelium, uptake in subjacent tissue cells, lysosomal enzyme activity, and substrate reduction (38 articles, 5 journal covers and/or editorials, 17 awards). To move this promising platform toward translation, we now will focus on: (a) enzyme encapsulation in biodegradable polymer nanocarriers and safer targeting moieties to minimize immune recognition, (b) incorporation of anti-phagocytic signals to minimize clearance, (c) tuning of the formulation parameters to optimize the balance between brain-lung targeting and explore combination therapy for enhanced effects, and (e) optimization of carrier degradation within lysosomal to avoid “polymer storage” upon chronic treatment. We have key results supporting these new directions and completion of a renewed project will significantly advance the opportunity for a more effective and safer treatment of NPD, and likely other LSDs.

概括由于遗传溶酶体，溶酶体储存（LSD）疾病包括50种致命疾病酶缺乏症，会影响大多数组织和伴侣对广泛的炎症表型。治疗是通过酶替代疗法（ERT）进行的，其中重组酶为静脉固醇。注入医院，对患者和卫生系统进行高烧伤（≥150,000$/患者 - 年）。尽管如此，ERT的成功仍仅限于几种影响肝脏，Sleen和Kidsneys的疾病，由于这些酶进入这些血液清除器官。但是，分离的组织分离从严格的内皮屏障（主要是肺部的大脑）的血液中阻碍。一个例子是A-B型NPD，这是由于酸而导致的鞘磷脂储存鞘磷脂酶（ASM）缺乏，导致过早死亡。 NPD-A有强大神经学的参与，无法通过ERT提高。 NPD-B主要影响肺部，尽管在ERT的帮助下，高剂量和剂量会引起免疫反应和抗性，以及另一个副作用。我们最初的奖项旨在将重组ASM定位为ICAM-1，蛋白质过表达炎症，并与跨越新的运输途径有关内皮并进入组织细胞的溶酶体。在上一个阶段，我们成功实现了我们的目标并改善了：大脑和肺靶向，在整个内皮上运输，在亚jaCACACACACESTER细胞，溶酶体酶活性和底物还原中摄取（38篇文章， 5个期刊封面和/或社论，17个奖项）。将这个承诺平台转移到翻译，我们现在将重点关注：（a）可生物降解聚合物中的酶封装纳米载体和更安全的靶向部分以最大程度地减少免疫认知，（b）掺入抗细胞信号以最大程度地减少清除率，（c）对公式参数调整到优化脑肺靶向和探索组合疗法之间的平衡增强的效果和（e）优化溶酶体内载体降解以避免“聚合物” 在长期治疗后的存储”。我们有关键的结果支持这些新方向和完成一个新项目的完成将大大促进更有效的机会以及对NPD以及可能其他LSD的安全处理。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting superoxide dismutase to endothelial caveolae profoundly alleviates inflammation caused by endotoxin.

DOI：
10.1016/j.jconrel.2017.12.025
发表时间：
2018-02-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Shuvaev VV;Kiseleva RY;Arguiri E;Villa CH;Muro S;Christofidou-Solomidou M;Stan RV;Muzykantov VR
通讯作者：
Muzykantov VR

Models and methods to evaluate transport of drug delivery systems across cellular barriers.