Transient knockdown of the ACE-2 Receptor using the RALA Technology for COVID-19

使用针对 COVID-19 的 RALA 技术瞬时敲除 ACE-2 受体

• 批准号: 55033
• 金额: $ 9.55万
• 依托单位: PHION THERAPEUTICS LTD
• 依托单位国家: 英国
• 项目类别: Feasibility Studies
• 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=55033
• 关键词: Transient; knockdown; ACE; Receptor; using

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) \[Turnbull 2020\]. 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 \[Leung 2020\]. 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 \[Kuba 2005\]. 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. Therefore with clear alignment to the specific theme of healthcare in this COVID-19 grant call, pHion 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 do not require cold chain storage can be stored for many months without losing functionality. The proposed 6 month pilot study is designed to demonstrate that the RALA/RNAi NPs can reduce ACE-2 receptor expression in human lung cells and then in vivo for a short period of time. The extension for impact funding builds upon the initial project by interrogating the safety profile of the RALA/RNAi NPs in vivo. This 3 month extension is designed to complete a study that measures both the toxicological and immunological response following single and multiple injections of the RALA/RNAi NPs in vivo. The outputs from this additional study will result in a commercially valuable data pack that demonstrates how safe the RALA technology is. The original project and the further impact study will provide evidence which is critical to secure future investment for the development of this therapeutic towards a Phase I trial. This short-acting RNAi therapy holds potential for any coronavirus outbreak that targets the ACE-2 receptor.

RNAi疗法有可能改变医疗保健干预措施，这一点在过去2年中批准了2种用于威胁生命的疾病的产品。RNAi疗法被设计为瞬时减少缺陷基因以用于治疗目的。这是一个快速增长的市场，临床试验中有109种基于RNAi的疗法（2018年7月）\[Turnbull 2020\]。然而，仍然存在围绕RNAi疗法的问题，包括到达适当的组织，然后确保细胞内递送到目的地位点。最近的研究还表明，患有糖尿病、高血压或吸烟者等基础健康状况的患者肺上皮中ACE-2受体数量增加[Leung 2020\]。研究表明，COVID-19利用ACE-2受体进入细胞，以产生更多的病毒颗粒，从而感染更多ACE-2受体阳性细胞\[Kuba 2005\]。ACE-2受体对许多生物功能起作用，但如果表达可以在短时间内降低，它可以降低病毒的感染性，并有助于平衡健康恢复。RNAi可用于瞬时降低该ACE-2受体的表达，但仅当存在适当的递送系统时。因此，在此次COVID-19拨款呼吁中，pHion与医疗保健的特定主题明确一致，开发了一种安全的RNAi递送解决方案，不会进一步加剧免疫系统，优先将治疗药物递送到肺部，并且具有成本效益，最终能够广泛采用RNAi疗法。创新的中心是使用一种名为RALA的肽，该肽被设计用于将RNAi浓缩成纳米颗粒（NP），这些纳米颗粒具有穿过细胞膜所必需的特性，从而逃脱内体，将货物高效地递送到细胞质中。在设计用于降低ACE-2表达的RNAi和RALA肽之间形成的NP不需要冷链储存，可以储存数月而不丧失功能性。所提出的6个月的初步研究旨在证明RALA/RNAi NP可以降低人肺细胞中的ACE-2受体表达，然后在体内短时间内降低。影响资金的扩展是在初始项目的基础上，通过询问RALA/RNAi NP在体内的安全性特征。此次为期3个月的延长旨在完成一项研究，该研究测量了体内单次和多次注射RALA/RNAi NP后的毒理学和免疫反应。这项额外研究的结果将产生一个具有商业价值的数据包，证明RALA技术的安全性。最初的项目和进一步的影响研究将提供证据，这对于确保未来投资开发这种治疗药物进行I期试验至关重要。这种短效RNAi疗法具有针对ACE-2受体的任何冠状病毒爆发的潜力。