Polymer particle catalysed miRNA therapeutics for HGSOC precision medicines

用于 HGSOC 精准医学的聚合物颗粒催化 miRNA 疗法

• 批准号: MR/Z503927/1
• 负责人: Lewis Francis
• 金额: $ 28.85万
• 依托单位: Swansea University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FZ503927%2F1
• 关键词: Polymer; particle; catalysed; miRNA; therapeutics

High grade serous ovarian cancer (HGSOC) is the most common type of Ovarian Cancer (OC), accounting for up to 80% of OC deaths, with only modest advances in OC clinical management over the past 3 decades, highlighting a requirement for modern therapeutics.[1,2] Treating cancer through the transfer of genetic material is one class of precision, advanced therapeutics, being developed. Indeed, miRNAs, whose deregulation has been associated with tumorigenic effects, now serve as disease diagnostic/prognostic biomarkers and are being explored for advanced gene therapy development.[3] At the moment there are no clinically approved gene therapies for OC.Due to the nature of RNAs and their pharmacokinetic limitations, they require a drug delivery system (DDS) for efficient cellular internalisation and targeted delivery. Using SMART polymer nanovectors (PEG-pTMC), we have developed a flexible DDS with favourable bioaccumulation in OC tumours, that demonstrate increased efficacy of chemotherapeutic drugs. Developed in line with the EMA GoNanoBioMat FRAMEWORK guidelines this platform is compatible with miRNA gene therapy payloads.[4]Leveraging publically available databases that aggregate current knowledge on disease associated and therapeutic miRNA expression, our team have developed a new in silico methodology for discovery of novel therpeutic miRNAs for advanced gene therapy development in OC.[4] This informatics tool has been used to strategically select three distinct single miRNAs that have shown in vitro anti-cancer efficacy while also allowing potential for synergy when combined in a "cocktail". Subsequently we have successfully encapsulated these miRNA(s) into PEG-pTMC nanoparticles and demonstrated their increased anti-cancer efficacy in established laboratory assays at Swansea University.Our over arching aim is to develop an innovative nanoparticle-encapsulated miRNA-based gene therapy for HGSOC, with the goal of transitioning from pre-clinical discoveries to a clinically applicable treatment. We have developed 4 clear aims for the project;Formulate and optimise PEG-pTMC miRNA cocktails, identified through our in silico assays, for maximised anticancer efficacy in HGSOC.Feedback wet lab in vitro data for iterative development of the in silico tools and optimised selection of miRNA cocktails.Validate anti-cancer efficacy, dose range and treatment shedules to inform pharmaceutical formulation and in vivo testing using a small-cohort mouse orthotopic studyDemonstrate clinical translational readiness and PEG-pTMC(miRNA) utility through the collection of anti-cancer metrics from pre-clinical models, including assessments of tumour growth inhibition, survival benefits, and potential off-target effects cross-referenced to pertinent regulatory frameworks.Applications and benefits; Benchmarking against the current DDS standard for miRNA, solid lipid NPs, which improve cellular penetration but still lead to systemic exposure, we will address both the clinical and product development needs in this gene therapy area. Upon project completion, the therapy will have comprehensive preclinical evidence to support clinical translation, underscoring the therapy's efficacy, safety, and readiness for the next stages of development. Moreover the informatics and separate DDS platforms (Technology Readiness Level 5/6), will have demonstrable applications to other solid tumour contexts (STCs), positioning our approach as an exemplar for gene therapy development in non-lipid based precision medicine catalogues, filling a significant gap in the current landscape of precision medicine.[5] Under the experienced leadership of Professor Francis, our interdisciplianry team combines advanced skill sets to support therapeutic product development, ensuring intellectual property (IP) protection and future translation profiling, toward DPFS funding in 2025.

高级别浆液性卵巢癌（HGSOC）是最常见的卵巢癌（OC）类型，占OC死亡的80%，在过去的30年中，OC临床管理仅取得了适度的进展，突出了对现代治疗的需求。[1，2]通过遗传物质转移治疗癌症是正在开发的一类精确的先进疗法。事实上，miRNAs，其失调与致瘤效应相关，现在作为疾病诊断/预后生物标志物，并正在探索先进的基因治疗开发。[3]目前还没有临床批准的OC基因疗法。由于RNA的性质及其药代动力学限制，它们需要药物递送系统（DDS）进行有效的细胞内化和靶向递送。使用SMART聚合物纳米载体（PEG-pTMC），我们开发了一种灵活的DDS，在OC肿瘤中具有良好的生物蓄积性，证明了化疗药物的疗效增加。根据EMA GoNanoBioMat FRAMEWORK指南开发，该平台与miRNA基因治疗有效载荷兼容。[4]利用医学上可用的数据库，这些数据库汇总了当前关于疾病相关和治疗性miRNA表达的知识，我们的团队开发了一种新的计算机方法，用于发现用于OC高级基因治疗开发的新型治疗性miRNA。[4]这种信息学工具已被用于战略性地选择三种不同的单一miRNA，这些miRNA已显示出体外抗癌功效，同时还允许在“鸡尾酒”中组合时具有协同作用的潜力。随后，我们成功地将这些miRNA封装到PEG-pTMC纳米颗粒中，并在斯旺西大学建立的实验室检测中证明了其增加的抗癌功效。我们的最终目标是开发一种创新的基于纳米颗粒封装的miRNA的HGSOC基因治疗，目标是从临床前发现过渡到临床适用的治疗。我们为该项目制定了四个明确的目标;通过我们的计算机模拟分析确定PEG-pTMC miRNA混合物，并对其进行配制和优化，以最大限度地提高HGSOC的抗癌功效。反馈湿实验室体外数据，用于计算机模拟工具的迭代开发和miRNA混合物的优化选择。剂量范围和处理流程，以告知药物配方和使用小队列小鼠原位研究的体内测试证明临床翻译准备和PEG-pTMC（miRNA）通过收集来自临床前模型的抗癌指标，包括肿瘤生长抑制评估、生存益处以及与相关监管框架交叉参考的潜在脱靶效应，实现实用性。以目前用于miRNA的DDS标准为基准，固体脂质纳米粒，其改善细胞渗透但仍导致全身暴露，我们会致力满足这基因治疗范畴的临床及产品发展需要。项目完成后，该疗法将有全面的临床前证据来支持临床转化，强调该疗法的有效性，安全性和下一阶段的开发准备。此外，信息学和单独的DDS平台（技术准备水平5/6）将在其他实体瘤背景（STC）中具有可证明的应用，将我们的方法定位为非脂质精准医学目录中基因治疗开发的典范，填补了当前精准医学领域的重大空白。[5]在弗朗西斯教授的经验丰富的领导下，我们的国际合作团队结合了先进的技能，以支持治疗产品的开发，确保知识产权（IP）保护和未来的翻译分析，在2025年对DPFS的资金。