Effective measurement and analysis for optimisation of Sixfold’s functionally enhanced Programmable Oligonucleotide Delivery System (PODS) for delivery of Cell and Gene therapeutics

“该项目将Sixfold的可编程寡核苷酸输送系统（PODS）与NPL在分析和测量纳米材料的物理化学和生物功能特性方面的深厚专业知识相结合。PODS已经证明了用于递送细胞和基因治疗剂（例如用于基因沉默的短干扰RNA（siRNA））的非常有前途的安全性。现在的目标是通过并入增强的功能性（包括内体逃逸机制）来优化siRNA-PODS的功效。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NPL独特的设施，设备和专业知识。这允许PODS的优化，可以无缝集成到高级治疗药物产品（ATMP）的开发中。由于siRNA对基因沉默具有高度的特异性和选择性，因此它有潜力为包括癌症在内的多种遗传疾病提供有效的治疗选择。Alnylam的siRNA疗法在2018年首次获得监管批准，[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用于将siRNA系统性递送至特定患病细胞的安全有效的系统。这一点得到了学术界和工业界的认可[2]。当前方法（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\[2\]，限制了可解决的疾病适应症的类型和数量，因此是次优的。PODS可以解决药物递送挑战，因为它们具有独特的生物相容性设计基于中央纳米支架，它可以用多种治疗剂和高度特异性的靶向分子功能化，这些分子识别癌症上的生物标志物，但不识别健康的生物标志物，临床前数据表明，siRNA-PODS的功效受限于它们在癌细胞进入时截留在细胞内囊泡（内体）中。这阻止了siRNA到达细胞质，在那里它们发挥其治疗作用。为了解决这个问题，Sixfold设计了新的内体逃逸机制。与NPL的合作将使增强功能性PODS（ef-PODS）的必要的高级分析和测量成为可能，使Sixfold能够有效地优化其治疗效果。这将加快临床前开发的完成，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，还针对其他疾病，为英国ATMP行业的竞争力做出贡献。[1\]Alnylam\_新闻稿\_30.08.18.\ [2]Karim ME等人制药2018”

"The project combines Sixfold's Programmable Oligonucleotide Delivery System (PODS) with NPL's deep expertise in analysis and measurement of physicochemical and biofunctional properties of nanomaterials. 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 optimise siRNA-PODS's efficacy by incorporating enhanced functionalitie(s) including endosomal escape mechanism(s). To that end, the project employs an iterative technical approach, takes advantage of the interdisciplinary expertise of the consortium and leverages NPL's unique facilities, equipment and know-how. This allows for optimisation of PODS that can be seamlessly integrated into the development of Advanced Therapy Medicinal Products (ATMPs). As such, the project enables PODS to quickly progress through preclinical development, and expediting commercialisation.Given their high specificity and 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 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 siRNA-PODS' efficacy is limited by their entrapment in intracellular vesicles (endosomes) upon cancer cell entry. This prevents siRNAs from reaching the cytoplasm where they exert their therapeutic effect. To address this, Sixfold has designed novel endosomal escape mechanism(s).The collaboration with the NPL will enable the necessary advanced analysis and measurement of the enhanced functionality PODS (ef-PODS), allowing Sixfold to effectively optimise their therapeutic effiacy. 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 for other diseases, contributing to the competitiveness of the UK's ATMP sector.\[1\]Alnylam\_Press Release\_30.08.18.\[2\]Karim\_ME\_et\_al.\_Pharmaceutic 2018"