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

• 批准号: 8098388
• 负责人: SILVIA MURO
• 金额: $ 37.5万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098388
• 关键词: Brain; Enzymes; Lung; Brain; Enzymes; Lung

Despite a low incidence, the economical burden of genetic diseases to families and the health system is extremely high, due to the cost of therapies ($100,000/patient-year) mostly suboptimal in alleviating these chronic conditions. This is the case for enzyme replacement therapies (ERTs) for treatment of lysosomal storage disorders (LSDs), prevalent genetic defects due to deficiency of lysosomal enzymes. ERT success is restricted to a few diseases affecting liver, spleen, and kidneys, where injected enzymes gain access via mechanisms of blood clearance. However, ERT delivery to the lungs, or brain for most common neurological LSDs, is hindered by the lack of affinity and transport of the enzymes to and into tissues. An example is ERT for Niemann-Pick disease (NPD) due to acid sphingomyelinase (ASM) deficiency, where lysosomal excess of sphingomyelin causes strong neurological disorder (type A phenotype) and affects lungs, liver and spleen (type B phenotype). Our goal is to develop strategies to improve ERT delivery to disease sites (lungs and brain). We propose to target ASM to intercellular adhesion molecule-1 (ICAM-1) expressed on the endothelium of all organs and cell targets in the parenchyma of tissues, and up-regulated in NPD. Our results indicate that classical endocytosis associated to vesicular transport from the blood to the tissue and the cell surface to lysosomes are defective in NPD, yet the non-classical pathway induced by ICAM-1 engagement by multivalent anti-ICAM/polystyrene prototype carriers is fully active in NPD. These prototypes enhance ASM targeting to lysosomes and sphingomyelin reduction in cultured endothelial cells and mice. A fraction of anti-ICAM prototype carriers are transported across endothelial cultures. We hypothesize that biocompatible ICAM-1- targeted carriers can provide vesicular transport of ASM across endothelial barriers (without affecting permeability) and endocytosis and lysosomal delivery in cells of the tissue parenchyma, attenuating NPD lung and brain phenotype. We will test this in cells and mouse models, using our new biocompatible PLGA carriers targeted to ICAM-1 by a peptide derived from its natural ligand, in Aims to evaluate and optimize: 1-Efficacy and safety of transendothelial transport, 2-Non-endothelial delivery, and 3-Effects in the NPD phenotype. The benefits of this strategy to transport therapeutics across endothelial barriers and into cells may transcend other LSDs and CNS treatments.

尽管发病率很低，但由于疗法的成本（100,000美元/患者年），遗传疾病的经济负担和卫生系统的经济负担非常高，主要是在减轻这些慢性病的情况下次优。酶替代疗法（ERT）就是这种情况，用于治疗溶酶体储存障碍（LSD），由于溶酶体酶的缺乏而导致普遍的遗传缺陷。 ERT成功仅限于影响肝脏，脾脏和肾脏的几种疾病，在这些疾病中，注射酶通过血液清除机制进入。然而，由于缺乏亲和力和将酶运输到组织中的亲和力和运输而阻碍了向肺部或大脑的ERT递送。一个例子是由于酸性鞘磷脂酶（ASM）缺乏引起的Niemann-Pick疾病（NPD），其中溶酶体过量的鞘磷脂过量会引起较强的神经系统疾病（A型表型），并影响肺，肝脏和脾脏（B型B表型）。我们的目标是制定策略来改善向疾病部位（肺和大脑）的递送。我们建议将ASM靶向在组织实质中所有器官和细胞靶的内皮上表达的细胞间粘附分子-1（ICAM-1），并在NPD中上调。我们的结果表明，从血液到组织和细胞表面到溶酶体的囊泡转运相关的经典内吞作用在NPD中有缺陷，但是由ICAM-1通过多价抗ICAM/Polystyrene Prototyper携带引起的非经典途径在NPD中完全活跃。这些原型增强了靶向溶酶体的ASM靶向，并减少培养的内皮细胞和小鼠的鞘磷脂。一小部分抗ICAM原型载体是在内皮培养物之间运输的。我们假设生物相容性的ICAM-1靶向载体可以提供ASM跨内皮屏障的囊泡转运（不影响渗透性），内吞作用和溶酶体在组织实质细胞中的细胞，减弱NPD肺和大脑表型。我们将在细胞和小鼠模型中使用我们的新生物相容性PLGA载体靶向ICAM-1的新生物相容性PLGA载体，其目的是评估和优化：1-效率和安全性和安全性的效率和安全性。这种策略在跨内皮屏障和细胞中运输治疗剂的好处可能会超越其他LSD和CNS治疗。