Developing a method for in vivo quantification and analysis of Sixfold’s Programmable Oligonucleotide Delivery System (PODS) for siRNA cancer therapy

开发用于 siRNA 癌症治疗的 Sixfold 可编程寡核苷酸输送系统 (PODS) 的体内定量和分析方法

• 批准号: 105544
• 金额: $ 2.95万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=105544
• 关键词: Developing; method; vivo; quantification; analysis

"The project combines Sixfold's Programmable Oligonucleotide Delivery System (PODS) with deep expertise of NML in quantitative bio-measurement and NPL in qualitative and quantitative advanced imaging to determine and optimise PODS in vivo profile. PODS have demonstrated a highly promising safety profile for delivery of Cell&Gene therapeutics such as short-interfering RNA (siRNA) for gene-silencing. The aim now is to complete preclinical studies and meet the requirements of the regulatory agencies by collecting more robust data on PODS' pharmacokinetics/dynamics profile. To that end, the project employs an iterative technical approach, takes advantage of the interdisciplinary expertise of the consortium and leverages NML's/NPL's unique facilities, equipment and know-how. This allows for optimisation, enabling PODS to quickly progress through preclinical development, and expediting commercialisation.Given their high specificity/selectivity for gene-silencing, siRNAs have the potential to provide effective treatment options for a variety of genetically-driven diseases including cancer. The first ever regulatory approval of Alnylam's siRNA therapy in 2018\[1\] has validated the clinical and commercial opportunity for such therapies. The major limiting factor for their further clinical and commercial success is the lack of safe and effective systems for systemic delivery of siRNAs to specific diseased cells. This is recognised by academia and industry\[2\]. Current approaches (viral-based/lipid-based) are sub-optimal given their limited specificity, toxicity, and complex/expensive manufacturing\[2\], limiting the type and number of addressable disease indications.PODS can address the drug delivery challenge given their unique, biocompatible design based on a central ""naked"" RNA nanoscaffold, which can be functionalised with multiple therapeutics and highly-specific targeting molecules that recognise biomarkers on cancer -but not healthy- cells.Preclinical data indicates a highly competitive safety profile of siRNA-PODS cancer therapy. However, to complete the preclinical studies and meet the requirements of the regulatory agencies, Sixfold must collect more robust data on PODS' pharmacokinetics/dynamics profile. Although Sixfold has performed biodistribution studies in rodents, the results of these experiments have not allowed for quantitative analysis on the composition of PODS, their by-products and their exact distribution in tissues.By utilising NML's and NPL's expertise, the project will enable the necessary advanced in vivo analysis/measurement of:(i)intact PODS versus by-products, (ii)spatial distribution and subcellular localisation in tissue. This would accelerate the completion of preclinical development, unlocking Sixfold's ability to generate first revenue from licensing agreements and expediting clinical development not only for our primary indication but also other diseases, contributing to the competitiveness of the UK's _Advanced Therapies_.\[1\]Alnylam\_Press Release\_30.08.18.\[2\]Karim\_ME\_et\_al.\_Pharmaceutic 2018"

“该项目将 Sixfold 的可编程寡核苷酸递送系统 (PODS) 与 NML 在定量生物测量方面的深厚专业知识以及 NPL 在定性和定量高级成像方面的深厚专业知识相结合，以确定和优化 PODS 体内概况。PODS 已证明在细胞和基因治疗药物（例如用于基因沉默的短干扰 RNA (siRNA)）的递送方面具有非常有前景的安全性。 现在的目标是通过收集有关 PODS 药代动力学/动力学概况的更可靠数据来完成临床前研究并满足监管机构的要求。为此，该项目采用迭代技术方法，利用联盟的跨学科专业知识，并利用 NML/NPL 独特的设施、设备和专业知识。这可以实现优化，使 PODS 能够快速完成临床前开发，并且 加速商业化。鉴于其基因沉默的高特异性/选择性，siRNA 有潜力为包括癌症在内的多种基因驱动疾病提供有效的治疗选择。 Alnylam 的 siRNA 疗法于 2018 年首次获得监管机构批准[1]，验证了此类疗法的临床和商业机会。其进一步临床和商业成功的主要限制因素是缺乏安全有效的系统递送系统 针对特定患病细胞的 siRNA。这已得到学术界和工业界的认可\[2\]。目前的方法（基于病毒/基于脂质）由于其有限的特异性、毒性和复杂/昂贵的制造\[2\]，因此不是最佳的，限制了可寻址疾病适应症的类型和数量。PODS 因其基于中心“裸”RNA 的独特、生物相容性设计，可以解决药物输送挑战 纳米支架，可以用多种疗法和高度特异性的靶向分子进行功能化，这些靶向分子可以识别癌症细胞上的生物标志物，但不能识别健康细胞上的生物标志物。临床前数据表明 siRNA-PODS 癌症治疗的安全性具有高度竞争力。然而，为了完成临床前研究并满足监管机构的要求，Sixfold 必须收集有关 PODS 药代动力学/动力学概况的更可靠的数据。虽然 Sixfold 已在啮齿动物中进行了生物分布研究，这些实验的结果无法对 PODS 的组成、其副产物及其在组织中的精确分布进行定量分析。通过利用 NML 和 NPL 的专业知识，该项目将实现必要的先进体内分析/测量：(i) 完整的 PODS 与副产物，(ii) 空间分布和亚细胞定位 在组织中。这将加速临床前开发的完成，释放 Sixfold 从许可协议中获得第一笔收入的能力，并加快临床开发，不仅针对我们的主要适应症，而且还针对其他疾病，从而有助于英国_Advanced Therapies_的竞争力。\[1\]Alnylam\_Press 发布 \_30.08.18.\[2\]Karim\_ME\_et\_al.\_Pharmaceutic 2018"