Efficient, controlled delivery of synthetic anion carriers to epithelial cells for CFTR replacement therapy

遗传性疾病囊性纤维化（CF）是由囊性纤维化跨膜传导调节因子（CFTR）基因的致病性变异引起的。大量的变体及其对CFTR表达和作为上皮阴离子通道的功能的复杂影响刺激了CF的通道替代治疗策略的发展。在以前的工作中，AP Davis和DN Sheppard教授（布里斯托大学）设计、合成并测试了人工脂质膜和细胞中的人工阴离子转运体（阴离子载体）。这项工作确定了反式萘烷阴离子载体具有有前途的生物活性，包括效力和持久性，而没有毒性作用。然而，许多在人工脂质膜中具有高活性的阴离子载体难以输送到细胞，认为它们需要特定的药物输送系统才能实现其治疗潜力。这个博士项目研究了使用基于AE Garcia-Bennett博士（麦考瑞大学）开发的介孔二氧化硅颗粒的纳米结构药物递送平台将阴离子载体递送到上皮细胞。这种用于将阴离子载体递送至CF上皮细胞的创新药物递送平台将促进阴离子载体的翻译作为CF的通道替代疗法。此外，该项目还提供了对职业发展至关重要的跨学科研究方面的优秀培训。它属于EPSRC医疗保健技术主题和化学生物学和生物化学研究领域的福尔斯。

The genetic disease cystic fibrosis (CF) is caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The large number of variants and their complex effects on CFTR expression and function as an epithelial anion channel have stimulated the development of channel replacement therapeutic strategies for CF. In previous work, Professors AP Davis and DN Sheppard (University of Bristol) designed, synthesized and tested artificial anion transporters (anionophores) in artificial lipid membranes and cells. This work identified trans-decalin anionophores with promising biological activity, including potency and persistence without toxic effects. However, many anionophores with high activity in artificial lipid membranes are poorly deliverable to cells, arguing that they require specific drug delivery systems to achieve their therapeutic potential. This PhD project investigates the delivery of anionophores to epithelial cells using nanostructured drug-delivery platforms based on mesoporous silica particles developed by Dr AE Garcia-Bennett (Macquarie University). This innovative drug-delivery platform for anionophore delivery to CF epithelial cells will facilitate the translation of anionophores as a channel replacement therapy for CF. Moreover, the project provides excellent training in interdisciplinary research important for career development. It falls within the EPSRC Healthcare Technologies theme and Chemical biology and Biological Chemistry research area.