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，用于将短干扰RNA （siRNA）基因沉默货物递送到特定细胞。通过利用合作伙伴Sixfold和Medicine Discovery Catapult （MDC）的跨学科和互补性专业知识，该项目允许快速的科学和商业进展，旨在与确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治疗靶点，具有高特异性和效力；而他们的易于制造允许快速领先优化\[1\]。因此，sirna有可能为包括癌症在内的多种疾病提供有效的治疗选择。Alnylam的siRNA治疗肝脏疾病在2018- 2019年首次获得监管机构批准\[1-2\]，这证实了这种疗法的临床和商业机会。然而，它们进一步成功的主要限制因素仍然是缺乏将sirna系统递送到特定病变细胞\[4\]的有效系统。目前的方法，主要是galnac偶联物、脂质纳米颗粒和病毒载体，由于其有限的细胞靶向特异性、载货能力、高毒性和复杂/昂贵的制造，限制了可治疗的疾病适应症的类型，因此不是最佳的。Mergo平台可以解决这一药物输送挑战，因为它基于中心RNA纳米支架的模块化设计，可以与治疗药物和靶向分子一起功能化，识别癌症细胞（但不是健康细胞）的生物标志物。虽然第一代Mergo在体外和体内都表现出了良好的结果，具有高度竞争力的安全性和有利的成本，但疗效仍有待优化。TARGET验证了一种新的货物附着系统，以增加Mergo的货物装载能力，从而提高效率。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，与病毒技术相比，Mergo代表了一个吸引人的机会，可以在蓬勃发展的基因治疗递送市场中占据很大一部分，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的发展。MDC在高级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要求的临床前数据包，通过许可实现快速商业化和临床进展。Sixfold广泛的知识产权组合和许可战略涉及整个生物制药供应链，为更广泛的英国生命科学领域提供多样化的利益。\[1\] 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＿11/ber＿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\.