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

“该项目将Sixfold的可编程寡核苷酸传递系统（PODS）与NML在定量生物测量和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在体内的轮廓。pod已被证明在细胞和基因疗法（如用于基因沉默的短干扰RNA (siRNA)）的递送方面具有很高的安全性。现在的目标是完成临床前研究，并通过收集更多关于PODS药代动力学/动力学概况的可靠数据来满足监管机构的要求。为此，该项目采用了迭代的技术方法，利用了联盟的跨学科专业知识，并利用了NML /NPL独特的设施、设备和专业知识。这允许优化，使pod能够通过临床前开发快速进展，并加速商业化。鉴于sirna对基因沉默的高特异性/选择性，sirna有可能为包括癌症在内的各种遗传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\[1\]，这证实了此类疗法的临床和商业机会。限制其进一步临床和商业成功的主要因素是缺乏安全有效的sirna系统递送到特定病变细胞的系统。这得到了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\[2\]，限制了可寻址疾病适应症的类型和数量，因此不是最佳的。pod可以解决药物递送的挑战，因为它们独特的、基于中心“裸”RNA纳米支架的生物相容性设计，可以用多种治疗方法和高度特异性的靶向分子进行功能化，这些分子可以识别癌症细胞（但不是健康细胞）上的生物标志物。临床前数据表明，siRNA-PODS癌症治疗具有高度竞争性的安全性。然而，为了完成临床前研究并满足监管机构的要求，Sixfold必须收集更多关于PODS药代动力学/动力学概况的可靠数据。虽然Sixfold在啮齿类动物中进行了生物分布研究，但这些实验的结果无法对pod的组成、副产品及其在组织中的确切分布进行定量分析。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pod与副产品，（ii）组织中的空间分布和亚细胞定位。这将加速临床前开发的完成，释放Sixfold从许可协议中获得首批收入的能力，加快临床开发，不仅针对我们的主要适应症，也针对其他疾病，有助于提高英国先进疗法的竞争力。\[1\] Alnylam＿Press Release＿30.08.18。\[2\] Karim＿ME＿et＿al。《药学2018》

"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"