Resilience-TARGET: RNA nanotechnology delivery platform for RNA therapies

TARGET旨在临床前验证Sixfold的可编程寡核苷酸递送系统Mergo，用于向特定细胞递送短干扰RNA（siRNA）基因沉默货物。通过利用合作伙伴-Sixfold和Medicine Discovery Catapult（MDC）-的跨学科和互补专业知识，该项目可以快速实现科学和商业进展，旨在与指定的制药公司进行早期研发合作和许可。与小分子和基于抗体的药物相比，siRNA可以作用于几乎不受限制的选择-否则“无法用药”-治疗靶点，具有高特异性和效力;而它们的易于制造允许快速的铅优化[1]。因此，siRNA具有为包括癌症在内的多种疾病提供有效治疗选择的潜力。Alnylam的siRNA疗法在2018-19年首次获得监管批准\[1-2\]，验证了此类疗法的临床和商业机会。然而，其进一步成功的主要限制因素仍然是缺乏将siRNA系统性递送至特定病变细胞的有效系统[4]。目前的方法，主要是GalNAc-缀合物、脂质纳米颗粒和病毒载体，由于其有限的细胞靶向特异性、货物装载能力、高毒性和复杂/昂贵的制造，限制了可寻址疾病适应症的类型，因此是次优的Mergo平台可以解决这种药物递送挑战，因为其模块化设计基于中央RNA纳米支架，它可以被治疗剂和靶向分子功能化，这些分子识别癌症细胞上的生物标志物，但不识别健康细胞。尽管第一代Mergo在体外和体内都取得了令人鼓舞的结果，具有极具竞争力的安全性和有利的成本，但其功效仍有待优化。TARGET验证了一种新型货物附着系统，以增加Mergo的货物装载能力，从而提高功效。这也将提高Mergo的多功能性和开发速度，即能够随时适应多种不同货物类型的交付，创造一个超越当前标准限制的智能交付系统。因此，Mergo代表了一个有吸引力的机会，可以抓住蓬勃发展的基因治疗市场的重要部分，并可以通过提高安全性，有效性和降低商品成本来加速其他先进治疗药物产品，MDC在先进的临床前成像方面的独特专业知识允许完成符合制药行业标准和快速商业化要求的临床前数据包Sixfold广泛的知识产权组合和许可策略涉及整个生物制药供应链，为更广泛的英国生命科学行业提供多样化的利益。[1] Lam J.K.W等人《分子核酸》2015年第4期第9卷：e252页。[2\]Alnylam\_Press\_release\_10\_August\_2018.\ [3\]Alnylam\_Press\_release\_20\_November\_2019.\ [4\]Payne\_D\__Nature_\_574\_S1\_2019\.

TARGET aims to preclinically validate Sixfold's Programmable Oligonucleotide Delivery System, Mergo, for delivery of short-interfering RNA (siRNA) gene silencing cargo to specific cells. By taking advantage of the interdisciplinary and complementary expertise of the partners --Sixfold and Medicine Discovery Catapult (MDC)-- the project allows for rapid scientific and commercial progress directed at early R&D collaboration and licensing with identified pharmaceutical companies.Compared to small molecule and antibody-based drugs, siRNAs can act on virtually unrestricted choice of --otherwise "undruggable"-- therapeutic targets, with high specificity and potency; while their easy manufacturing allows for rapid lead optimization \[1\]. As such, siRNAs have the potential to provide effective treatment options for diverse diseases including cancer. The first regulatory approvals of Alnylam's siRNA therapies for liver disorders in 2018-19 \[1-2\] have validated the clinical and commercial opportunity for such therapies. However, the major limiting factor for their further success remains the lack of effective systems for systemic delivery of siRNAs to specific diseased cells \[4\]. Current approaches, primarily GalNAc-conjugates, lipid nanoparticles and viral vectors, are sub-optimal given their limited cell targeting specificity, cargo loading capacity, high toxicity, and complex/expensive manufacturing that limit the type of addressable disease indications.The Mergo platform can address this drug delivery challenge given its modular design based on a central RNA nanoscaffold, which can be functionalised with therapeutics and targeting molecules that recognise biomarkers on cancer -but not healthy- cells. Although first-generation Mergo demonstrated promising _in vitro_ and _in vivo_ results, with highly competitive safety and favourable cost profiles, the efficacy remains to be optimised.TARGET validates a novel cargo attachment system to increase Mergo' cargo loading capacity, allowing for improvements in efficacy. This will also enhance Mergo versatility and speed of development, i.e. ability to readily adapt to delivery of multiple, different cargo types, creating an intelligent delivery system that goes beyond the limitations of current standards. As such, Mergo represent an attractive opportunity to capture a significant portion of the thriving gene therapy delivery market and could accelerate other Advanced Therapy Medicinal Products, through improved safety, efficacy and reduced cost of goods, especially compared to viral technologies.MDC's unique expertise in advanced preclinical imaging allows for completion of preclinical datapack to pharmaceutical industry standards and requirements for rapid commercialization and clinical advancement via licensing.Sixfold's broad IP portfolio and licensing strategy engage the entire biopharmaceutical supply chain, providing diverse benefits to the wider UK life sciences sector.\[1\]Lam\_J.K.W\_et\_al.\__Mol\_Ther\_Nucleic\_Acids_\_2015\_4(9):e252.\[2\]Alnylam\_Press\_release\_10\_August\_2018.\[3\]Alnylam\_Press\_release\_20\_November\_2019.\[4\]Payne\_D\__Nature_\_574\_S1\_2019\.