Targeted replacement of defective lysosomal enzymes in the lung and brain

摘要 溶酶体储存障碍包括大约50种由遗传性溶酶体引起的致命性疾病。 酶缺乏，影响大多数组织，并与广泛的炎症表型有关。 治疗是通过酶替代疗法(ERT)，即静脉注射重组酶。 注入医院，给患者和医疗系统带来沉重负担(≥$150,000/患者- 年)。尽管如此，ERT的成功仅限于影响肝、脾和肾脏的几种疾病， 因为这些酶可以进入这些血液清除器官。然而，递送到分开的组织 来自血液的一层紧密的内皮屏障(主要是大脑，在某种程度上是肺) 受阻了。A-B型NPD就是一个例子，这是由于酸导致的神经鞘蛋白储存 鞘磷脂酶(ASM)缺乏，导致过早死亡。NPD-A有很强的 神经受累，ERT未见改善。NPD-B主要影响肺部，尽管 在ERT的帮助下，高和频繁的剂量会引起免疫反应和耐药性，以及 其他副作用。我们最初的奖项集中在将重组ASM靶向ICAM-1，a 在炎症中过度表达的蛋白质与一条新的跨血管运输路线有关 内皮细胞和组织细胞的溶酶体。经过前一段时间，我们成功地 实现了我们的目标并改进了：脑和肺靶向，血管内皮细胞转运， 下层组织细胞摄取、溶酶体酶活性和底物还原(38篇文章， 5个期刊封面和/或社论，17个奖项)。将这个前景看好的平台推向 现在我们将重点介绍：(A)可生物降解聚合物中的酶 纳米载体和更安全的靶向部分，以尽量减少免疫识别，(B)纳入 抗吞噬信号，以最大限度地减少清除，(C)调整配方参数以 优化脑肺靶向平衡，探索综合治疗 增强效果，以及(E)优化溶酶体内载体的降解，以避免“聚合物” 长期治疗时的“储存”。我们有支持这些新方向的关键成果，并且 新项目的完成将极大地推进更有效的 以及对NPD和可能其他LSD的更安全的治疗。

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.