Automated Production of RALA/Nucleic Acid Nanoparticles from Bench to Patient Dose

从实验室剂量到患者剂量的 RALA/核酸纳米颗粒的自动化生产

• 批准号: 78128
• 金额: $ 32.47万
• 依托单位: PHION THERAPEUTICS LTD
• 依托单位国家: 英国
• 项目类别: Collaborative R&D
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=78128
• 关键词: Automated; Production; RALA; Nucleic; Acid

RNAi therapeutics have the potential to transform healthcare interventions as evidenced by the approval of 2 products in the last 2 years for life threatening diseases. RNAi therapy is designed to transiently reduce a defective gene for therapeutic purposes. It is a rapidly growing market with 109 RNAi based therapeutics in clinical trials (July 2018) \[Wu X. and Turnball A.P. 2018\]. However, there are still issues that surround the RNAi therapeutics which include getting to the appropriate tissue and then ensuring intracellular delivery to the destination site. Recent studies have also indicated that those with underlying health conditions such as diabetes, high-blood pressure or smokers have an increased number of ACE-2 receptors in the lung epithelium \[Leung J.M, 2020\]. Studies have revealed that COVID-19 uses the ACE-2 receptor to enter cells in order to produce more viral particles that can infect more ACE-2 receptor positive cells \[Kuba K. 2005\]. The ACE-2 receptor plays a role for many biological functions but if expression could be lowered for a short period of time it could reduce the infectivity of the virus and help tip the balance towards healthy recovery. RNAi could be used to transiently reduce expression of this ACE-2 receptor but only if there is an appropriate delivery system. pHion (Belfast SME) have developed a solution for RNAi delivery that is safe, does not further exacerbate the immune system, preferentially delivers the therapeutic to the lung and is cost-effective, ultimately enabling widespread adoption of the RNAi therapy. The innovation centres around the use of a peptide termed RALA that is designed to condense RNAi into nanoparticles (NPs) that have the properties necessary to cross cell membranes, escape endosomes delivering the cargo to the cytoplasm with high efficiency. The NPs formed between the RNAi which is designed to reduce ACE-2 expression and the RALA peptide NPs do not require cold chain storage and can be stored for many months without losing functionality. However, we do not as yet have a methodology in place to support the large-scale production of these NPs. Indeed, for the nucleic acid industry, one of the greatest hurdles will be the manufacture of novel therapeutics. Therefore with clear alignment to the specific theme of challenges as a result of COVID-19, this project is designed to accelerate and optimise the scale-up of the RALA/RNAi therapeutic to patient doses in order to be 'future ready'. The proposed 9 month project is designed to develop the optimal conditions for the automated production of functional NPs using microfluidics that can be readily transferred to clinical doses. We will also develop the optimal lyophilisation process to ensure a highly stable functional product. Finally, with regulatory framework in place and proof that we can transfer our process externally to scale up to clinical doses, we will be well positioned to take this therapy to the clinic and to position RALA as the go-to delivery system for RNAi therapeutics to the lung.

RNAi疗法有可能改变医疗干预措施，过去两年批准了两种产品，用于治疗危及生命的疾病。RNAi治疗的目的是为了治疗目的而暂时减少缺陷基因。这是一个快速增长的市场，有109种基于RNAi的疗法正在进行临床试验(2018年7月)[Wu X.和Turnball A.P.2018]。然而，围绕RNAi疗法仍然存在一些问题，包括到达适当的组织，然后确保细胞内递送到目的地。最近的研究还表明，那些有潜在健康状况的人，如糖尿病、高血压或吸烟者，肺上皮细胞中ACE-2受体的数量增加[梁建民，2020]。研究表明，新冠肺炎利用血管紧张素转换酶-2受体进入细胞，以产生更多的病毒颗粒，从而感染更多血管紧张素转换酶-2受体阳性细胞[库巴K.2005]。ACE-2受体在许多生物学功能中发挥作用，但如果能够在短时间内降低表达，就可以降低病毒的传染性，帮助平衡朝着健康恢复的方向发展。RNAi可以用来暂时减少这种ACE-2受体的表达，但前提是有合适的递送系统。PHION(贝尔法斯特SME)已经开发出一种安全的RNAi传递解决方案，该解决方案不会进一步加剧免疫系统，优先将治疗药物输送到肺部，并且具有成本效益，最终使RNAi疗法得以广泛采用。创新的核心是使用一种名为Rala的多肽，这种多肽旨在将RNAi浓缩成纳米颗粒(NPs)，这些纳米颗粒具有穿过细胞膜、高效地逃脱内体将货物运送到细胞质所需的特性。在旨在减少ACE-2表达的RNAi和Rala肽NPs之间形成的NPs不需要冷链储存，可以储存许多个月而不会失去功能。然而，我们目前还没有一套方法来支持这些核电站的大规模生产。事实上，对于核酸行业来说，最大的障碍之一将是新型疗法的制造。因此，该项目明确地与新冠肺炎带来的挑战这一特定主题保持一致，旨在加快和优化RALA/RNAi疗法扩大到患者剂量的过程，以便“为未来做好准备”。拟议的9个月项目旨在开发使用微流体自动化生产功能性NPs的最佳条件，这些微流体可以很容易地转移到临床剂量。我们还将开发最佳的冷冻干燥工艺，以确保产品具有高度稳定的功能。最后，随着监管框架的到位，以及我们可以将我们的过程转移到外部以扩大临床剂量的证据，我们将处于有利地位，将这种疗法带到临床，并将Rala定位为RNAi疗法到肺的首选递送系统。