Development of the next generation of lipid nanoparticles for gene therapy

开发用于基因治疗的下一代脂质纳米颗粒

• 批准号: 463247-2014
• 负责人: Tieleman, Peter
• 金额: $ 9.29万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Strategic Projects - Group
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=577034
• 关键词: Development; next; generation; lipid; nanoparticles

Lipid nanoparticles (LNPs) are a revolutionary tool for drug delivery, functional genomics and other applications in biotechnology and medicine. They are on the verge of enabling one of the dream applications of personalized medicine: individual gene therapy in diseases such as cancer. Knowledge of the "rogue" genes responsible for tumour growth is substantial but there remains a number of significant obstacles to effectively turning these genes off or "silencing" them. The most promising gene therapy approach utilizes short pieces of double stranded RNA (siRNA) whose sequence allows it to bind to the cancer gene's messenger RNA, after which a natural cellular mechanism degrades it. Following intracellular delivery siRNAs have demonstrated abilities to silence specific genes in vitro. However, the use of siRNA in vivo requires sophisticated delivery technologies, since "naked" siRNAs are rapidly broken down in the circulation, do not accumulate at disease sites and cannot penetrate target cell membranes to reach their intracellular sites of action. Encapsulating siRNA in an LNP protects the siRNA from degradation in the bloodstream, and enables the internalization of the siRNA within the cell via endocytosis. However, considerable work remains to increase the practical use of LNPs. The nanostructure of the LNP siRNA systems and the functional roles of the five different lipid components they contain are not well understood, impeding efforts to develop next generation systems that are stable, can be targeted to different tissues, are straightforward to manufacture, and meet regulatory requirements. In this project, we will use computer modelling and biophysical characterization to investigate the role of the different components in determining the structure, size, targeting properties and the endosomal release mechanism of LNPs. We will test our knowledge in the design and manufacture of new LNPs. This will lead to improved rational design technology for LNPs that will greatly expand their use as anti-cancer drugs and functional genomics tools, with extensive opportunities for commercialization of both technology, through our partner Precision NanoSystems, and the development of drugs for specific forms of cancer.

脂质纳米粒子 (LNP) 是药物输送、功能基因组学以及生物技术和医学其他应用的革命性工具。他们即将实现个性化医疗的梦想应用之一：癌症等疾病的个体基因治疗。对负责肿瘤生长的“流氓”基因的了解很丰富，但有效关闭或“沉默”这些基因仍然存在许多重大障碍。最有前途的基因治疗方法利用双链 RNA (siRNA) 的短片段，其序列使其能够与癌症基因的信使 RNA 结合，然后自然细胞机制将其降解。细胞内递送后，siRNA 已被证明能够在体外沉默特定基因。然而，在体内使用 siRNA 需要复杂的递送技术，因为“裸露”的 siRNA 在循环中会迅速分解，不会在疾病部位积聚，也无法穿透靶细胞膜到达其细胞内作用位点。将 siRNA 封装在 LNP 中可保护 siRNA 免于在血流中降解，并通过胞吞作用使 siRNA 内化到细胞内。然而，为了提高 LNP 的实际使用率，仍有大量工作要做。 LNP siRNA 系统的纳米结构及其所含五种不同脂质成分的功能作用尚不清楚，这阻碍了开发稳定、可靶向不同组织、易于制造并满足监管要求的下一代系统的努力。在这个项目中，我们将利用计算机建模和生物物理表征来研究不同成分在确定 LNP 的结构、大小、靶向特性和内体释放机制中的作用。我们将测试我们在新型 LNP 的设计和制造方面的知识。这将导致 LNP 的合理设计技术得到改进，从而极大地扩展其作为抗癌药物和功能基因组学工具的用途，并通过我们的合作伙伴 Precision NanoSystems 为这两种技术的商业化提供广泛的机会，并开发针对特定形式癌症的药物。