RAPOD: Rapid Assembly of Programmable Oligonucleotide Delivery systems for increased gene therapeutic load

RAPOD旨在扩大Sixfold可编程寡核苷酸递送系统（PODS）的药物递送能力，通过增加治疗负荷，将短干扰RNA （siRNA）基因沉默货物递送到特定的癌细胞。通过利用合作伙伴/分包商（Sixfold和SEDA）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。2018-19年，Alnylam siRNA治疗肝脏疾病的首批监管批准** \[2-3\] **验证了此类治疗的临床和商业机会。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的有效系统** \[4\] **。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。pod可以解决这一药物递送挑战，因为它们基于中心RNA纳米支架的模块化设计，可以用治疗药物和靶向分子功能化，识别癌症细胞（但不是健康细胞）上的生物标志物。虽然第一代pod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，但功效仍有待优化。RAPOD将致力于实现三个主要目标：1)**使用三种完全不同的技术方法**提高我们的pod技术的治疗负荷能力** 2)以**环境可持续的方式**，重点是减少API，浪费和试剂消耗3)制定**战略研发战略**，通过最大化可用资源加速pod临床前过渡到ind启用阶段。这也将提高pod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，pod代表了一个有吸引力的机会，可以占据蓬勃发展的基因治疗递送市场的很大一部分，并可以通过提高安全性、有效性和降低商品成本，特别是与病毒技术相比，加速其他先进治疗药物产品（ATMP）的发展。SEDA在提供众多产品的审批，商业化和随后的产品维护方面的独特专业知识允许pod研发战略的战略发展，以满足制药行业标准和要求，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\。

RAPOD aims to expand the drug delivery capabilities of Sixfold's Programmable Oligonucleotide Delivery System (PODS) for delivery of short-interfering RNA (siRNA) gene silencing cargo to specific cancer cells by increasing therapeutic loading capacity. By taking advantage of the interdisciplinary and complementary expertise of the partner/subcontractor --Sixfold and SEDA-- 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 **\[2-3\]** 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.PODS can address this drug delivery challenge given their 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 PODS demonstrated promising _in vitro_ and _in vivo_ results, with highly competitive safety and favourable cost profiles, the efficacy remains to be optimised.RAPOD will aim to address three main objectives: 1) **increase the therapeutic loading capacity** of our PODS technology using three radically different technological approaches 2) in an **environmentally sustainable way** with a focus on reducing API, waste and reagent consumption and 3) devising a **strategic R&D strategy** to accelerate PODS preclinical transition to IND-enabling stage by maximising resources available. This will also enhance PODS 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, 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.SEDA's unique expertise in delivering numerous products to approval, commercialisation and subsequent product maintenance allows for strategic development of PODS R&D strategy 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\.