55033Transient knockdown of the ACE-2 Receptor using the RALA Technology for COVID-19ClosedFeasibility StudiesInnovate UKRNAi 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.