Leveraging RNA nanotechnology for next-generation gene delivery systems

利用 RNA 纳米技术构建下一代基因传递系统

• 批准号: MR/T04442X/1
• 负责人: Ioanna Mylonaki
• 金额: $ 108.66万
• 依托单位: Sixfold Bioscience Ltd
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT04442X%2F1
• 关键词: Leveraging; RNA; nanotechnology; next; generation

Can we built efficient gene delivery systems to target the brain? Gene therapy offers the promise to effectively revert the cause of inherited and acquired brain diseases. However, the brain is arguably the most challenging organ to target with therapeutic agents, especially large-size gene therapeutics. This is due to the existence of the blood brain barrier (BBB) - a highly selective border separating the blood circulation from the brain, formed by a continuous layer of sealed endothelial cells embedded in the capillary basement membrane. The BBB physiologically protects the neurons from neurotoxic factors present in the bloodstream, but also prevents exogenously administered medications to reach their target of action. Non-targeting brain therapies could not only result in poor efficacy of the treatment, but also in side effects due to the accumulation of toxic drugs in other organs, encumbering the life of the patient. Lipid nanoparticles were thought to cross the BBB, thanks to their charge and size by abortpion mediated endocytosis or transcytosis. But this approach failed to provide efficient delivery, testified by the lack of approved gene therapies targeting the brain.Can we use nucleic acids as gene delivery systems to target the brain? Nucleic acids are unstable natural polymers that degrade by nucleases upon intravenous injection and thus far were considered unsuitable for use as drug delivery vehicles. Yet, they have inherent properties to accommodate spatially arranged molecules and controlled stoichiometry for precise shape and size nanoparticles, crucial for an efficient tissue and cell targeting. The new approach involves the introduction of nuclease stable RNA nanoparticles, based on Sixfold's Ltd patent portfolio for the exploitation of DNA and RNA-based nanoparticles and targeting molecules including, but not limited to, aptamers, for the delivery of selected gene therapeutics. In preliminary studies, these particles have shown to accumulate in the brain. The research programme focuses on the assessment of the causal relationship between RNA nanoparticles charge, lipophilicity and size; to tissue/cell targeting. The nature of repetitive units (nucleotides) of nucleic acids, allows for precise design of the delivery systems in silico and prediction of the nanoparticle behaviour using Machine Learning. This offers a high degree of flexibility to create an on-demand platform for tissue targeting and reduce the physical experimentation. A toolbox of methods allowing for the nanoparticles stoichiometric characterization and biodistribution monitoring imaging will be developed. Preclinical demonstrators of the platform will be assessed thanks to the engagement of pioneering research groups working on animal models on neurodegenerative diseases including Parkinson's and Kennedy's (spinal bulbar muscular atrophy) diseases.

我们能建立有效的基因传递系统来靶向大脑吗？基因治疗有望有效逆转遗传性和获得性脑部疾病的病因。然而，大脑可以说是最具挑战性的器官靶向与治疗剂，特别是大尺寸的基因治疗。这是由于血脑屏障（BBB）的存在-一种高度选择性的边界，将血液循环与大脑分开，由嵌入毛细血管基底膜中的连续密封内皮细胞层形成。血脑屏障在生理上保护神经元免受血流中存在的神经毒性因子的影响，但也阻止外源性给药药物到达其作用靶点。非靶向脑治疗不仅会导致治疗效果不佳，还会因毒性药物在其他器官中蓄积而产生副作用，危及患者的生命。由于脂质纳米颗粒的电荷和大小，脂质纳米颗粒被认为通过胞吞作用或胞吞作用穿过BBB。但是，这种方法未能提供有效的传递，缺乏批准的靶向大脑的基因疗法证明了这一点。我们可以使用核酸作为靶向大脑的基因传递系统吗？核酸是不稳定的天然聚合物，其在静脉内注射时被核酸酶降解，并且迄今为止被认为不适合用作药物递送载体。然而，它们具有固有的性质，以适应空间排列的分子和控制化学计量的精确形状和大小的纳米颗粒，这对于有效的组织和细胞靶向至关重要。新方法涉及引入核酸酶稳定的RNA纳米颗粒，基于Sixfold的Ltd专利组合，用于开发基于DNA和RNA的纳米颗粒和靶向分子，包括但不限于适体，用于递送选定的基因治疗剂。在初步研究中，这些颗粒已被证明在大脑中积累。该研究计划的重点是评估RNA纳米颗粒电荷，亲脂性和大小之间的因果关系;组织/细胞靶向。核酸的重复单元（核苷酸）的性质允许在计算机上精确设计递送系统，并使用机器学习预测纳米颗粒行为。这提供了高度的灵活性，以创建用于组织靶向的按需平台并减少物理实验。一个工具箱的方法，允许纳米粒子的化学计量表征和生物分布监测成像将被开发。该平台的临床前示范将得到评估，这要归功于致力于神经退行性疾病动物模型的先驱研究小组的参与，包括帕金森病和肯尼迪病（脊髓延髓肌萎缩症）。