Effective analysis and manipulation of the protein corona - increasing the efficacy of Sixfold’s delivery system for Cell and Gene therapeutics

有效分析和操纵蛋白质电晕 - 提高 Sixfold 细胞和基因治疗递送系统的功效

• 批准号: 106009
• 金额: $ 4.7万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=106009
• 关键词: Effective; analysis; manipulation; protein; corona

The project combines Sixfold's Programmable Oligonucleotide Delivery System (PODS) with the unique and deep expertise of LGC in quantitative bio-measurement of proteins, and NPL in analysis and measurement of physicochemical and biofunctional properties of nanomaterials, including advanced imaging. 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 a protein corona (PC) manipulation module. To that end, the project employs an iterative technical approach, takes advantage of the interdisciplinary expertise of the consortium and leverages LGC's/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), 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 (primarily viral- and 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 a highly competitive safety profile of siRNA-PODS cancer therapy. However, the gene-silencing efficacy remains to be optimised. siRNA-PODS' efficacy is limited by recruitment of PC onto PODS upon intravenous administration. The PC can dramatically influence the physical properties, pharmacokinetics and pharmacodynamics of nanoparticles \[3\].By utilising LGC's/NPL's expertise, the project enables the necessary advanced (i) proteomic, (ii) morphological and (iii) functional profiling of PC-bound-PODS, allowing for incorporation of optimised PC manipulation module(s) for enhanced therapeutic efficacy. 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.\[3\]Nguyen\_VH\_&\_Lee\_BJ\_Int\_J\_Nanomedicine\_2017\.

该项目将Sixfold的可编程寡核苷酸输送系统（PODS）与LGC在蛋白质定量生物测量方面的独特而深厚的专业知识以及NPL在分析和测量纳米材料的物理化学和生物功能特性（包括先进的成像）方面的专业知识相结合。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。现在的目标是通过整合蛋白质冠（PC）操作模块来优化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LGC/NPL独特的设施，设备和专业知识。这使得PODS的优化可以无缝地集成到先进治疗药物产品（ATMP）的开发中，使PODS能够通过临床前开发快速进展，并加快商业化。鉴于其对基因沉默的高度特异性/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]。当前方法考虑到它们有限的特异性、毒性和复杂/昂贵的制造[2]，PODS（主要基于病毒和脂质）是次优的，限制了可寻址疾病适应症的类型和数量。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癌症疗法的高度竞争性安全性概况。然而，基因沉默的功效仍有待优化。siRNA-PODS的功效受到静脉内施用时PC募集到PODS上的限制。PC可以极大地影响纳米颗粒的物理性质、药代动力学和药效学[3]。通过利用LGC/NPL的专业知识，该项目能够实现PC结合PODS的必要的先进的（i）蛋白质组学，（ii）形态学和（iii）功能分析，允许并入优化的PC操作模块以增强治疗效果。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等人制药业_2018年。[3\]Nguyen\_VH\_&\_Lee\_BJ\_Int\_J\_Nanomedicine\_2017\.