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

RAPOD：快速组装可编程寡核苷酸递送系统以增加基因治疗负荷

• 批准号: 92338
• 金额: $ 10.06万
• 依托单位: SIXFOLD BIOSCIENCE LTD.
• 依托单位国家: 英国
• 项目类别: Collaborative R&D
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=92338
• 关键词: RAPOD; Rapid; Assembly; Programmable; Oligonucleotide

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\.

RAPOD旨在扩大Sixfold的可编程寡核苷酸递送系统（PODS）的药物递送能力，通过增加治疗负载能力将短干扰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-的跨学科和互补专业知识，该项目允许快速的科学和商业进展，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，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;同时其易于制造允许快速铅优化 **\[1\]**。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 **\[2-3\]**，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/昂贵的制造而不是最佳的，这限制了可寻址疾病适应症的类型。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PODS在体外和体内试验中显示出良好的效果，具有高度竞争力的安全性和有利的成本，但其功效仍有待优化。RAPOD将致力于解决三个主要目标：1）** 使用三种完全不同的技术方法 ** 提高我们PODS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、废物和试剂消耗; 3）制定 ** 战略研发战略 **，通过最大限度地利用可用资源，加速PODS临床前向IND启动阶段的过渡。这也将提高极轨道密度扫描系统的多功能性和发展速度，即能够随时适应多种不同货物类型的交付，创造一个超越现有标准限制的智能交付系统。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（特别是与病毒技术相比）来加速其他高级治疗药物产品（ATMP）。SEDA在提供众多产品批准方面的独特专业知识，商业化和随后的产品维护允许PODS R&根据制药行业标准和要求制定战略，通过许可实现快速商业化和临床进展。该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\.