TARGET: RNA nanotechnology delivery platform for gene therapies, towards commercialization in cancer

TARGET旨在临床前验证Sixfold的可编程寡核苷酸递送系统（PODS），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，该项目得以实现快速的科学和商业进展，与小分子或基于抗体的药物相比，siRNAs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;而它们的制造容易，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安全有效的系统将siRNA系统性递送到特定的病变细胞[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/昂贵的制造而不是最佳的，这限制了可寻址疾病适应症的类型和数量。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。Sixfold的第一代PODS展示了良好的效果。TARGET扩展了PODS的实用性，并创建了一个超越当前标准限制的智能和多功能交付系统。因此，PODS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递送市场的重要部分，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品（ATMP），特别是与病毒技术相比。通过引入MDC在先进临床前成像方面的独特专业知识，TARGET可以完成符合制药行业标准的全面临床前数据包，以实现快速商业化和临床进展。Sixfold广泛的知识产权组合和业务战略涉及整个生物制药供应链，为更广泛的英国生命科学部门提供多样化的利益。[1] Lam J.K.W等人Mol\_Ther\_Nucleic\_Acids\_2015\_4（9）：e252.\ [2\] Alnylam\_Press\_release\_2018年8月10日\[3\] Alnylam\_Press\_release\_2019年11月20日。\ [4\]Payne\_D\_Nature\_574\_S1\_2019\.

TARGET aims to preclinically validate Sixfold's Programmable Oligonucleotide Delivery System (PODS) 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.Compared to small molecule or 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 a variety of 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 safe and 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 and number of addressable disease indications.PODS can address this drug delivery challenge given their modular design based on a central nanoscaffold, which can be functionalised with therapeutics and targeting molecules that recognise biomarkers on cancer -but not healthy- cells. Sixfold's first-generation PODS demonstrated promising results.TARGET expands PODS utility and creates an intelligent and versatile delivery system that goes beyond the limitations of current standards. As such, PODS represent an attractive opportunity to capture a significant portion of the thriving gene therapy delivery market and could accelerate other Advanced Therapy Medicinal Products (ATMP), through improved safety, efficacy and reduced cost of goods, especially compared to viral technologies. By bringing MDC's unique expertise in advanced preclinical imaging, TARGET allows for completion of a comprehensive preclinical datapack to pharmaceutical industry standards, for rapid commercialization and clinical advancement.Sixfold's broad IP portfolio and business 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\.