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.

高级浆液卵巢癌（HGSOC）是最常见的卵巢癌类型（OC），占OC死亡的80％，在过去30年中OC临床管理的进步仅适度，突出了对现代疗法的需求。[1,2]通过转移遗传材料是一种精确的治疗癌症，是一种精确的治疗，是一种精确的饮食，是一种先进的饮食，是一种先进的饮食学，是一种先进的培训。的确，miRNA的放松管制与致瘤作用有关，现在是疾病诊断/预后生物标志物，正在探索以进行晚期基因治疗的发展。[3]目前，尚无对RNA的性质及其药代动力学局限性的临床认可的基因疗法。使用智能聚合物纳米分离器（PEG-PTMC），我们在OC肿瘤中开发了具有良好生物蓄积的柔性DD，这表明化学治疗药物的疗效提高。根据EMA Gonanobiomat框架的开发，该平台与miRNA基因疗法有效载荷兼容。[4]利用公开可用的数据库来汇总有关疾病相关和治疗性miRNA表达的当前知识，我们的团队开发了一种新的Silico方法论，可以发现新型治疗性mirnas对先进基因的新型基因疗法开发，以实现OC的高级基因疗法。该信息学工具已被用来策略性地选择三种不同的单个miRNA，这些miRNA在体外显示了抗癌功效，同时还允许在“鸡尾酒”中合并时具有协同作用。随后，我们成功地将这些miRNA封装到PEG-PTMC纳米粒子中，并证明了它们在斯旺西大学的既定实验室测定中提高了抗癌功效。您的拱门目的是开发一种基于基于HGSoc的HGSOC的创新纳米粒子型MiRNA基因治疗，并在临床上进行过渡性，以实现临床量的临床量。我们已经为该项目开发了4个明确的目标；通过我们的硅硅测定法确定并优化PEG-PTMC miRNA鸡尾酒，以最大程度地提高HGSOC的抗癌功效。反馈湿湿实验室在体外数据迭代数据，用于迭代的迭代开发，以便在硅胶工具中及时进行了治疗和优化的Mirna Cocktial cockity antipare cocktial antipare cockity antipare cockingsy offial-cancoce andipose抗癌，并取代了抗癌症，并取代了抗癌症，并取代了抗癌作用。使用小型小鼠原位研究的体内测试通过收集临床模型的抗癌指标，包括肿瘤生长抑制，生存益处和潜在的非目标效应，跨越了对事物的框架的影响和效果，包括评估肿瘤生长抑制，生存效果和潜在的效果。针对MiRNA，固体脂质NP的当前DDS标准的基准测试，从而改善了细胞渗透但仍会导致全身暴露，我们将解决该基因治疗区域的临床和产品开发需求。项目完成后，该疗法将有全面的临床前证据，以支持临床翻译，强调疗法在下一个发展阶段的疗效，安全性和准备就绪。此外，信息学和单独的DDS平台（技术准备就绪水平5/6）将在其他实体瘤环境（STC）中有明显的应用，将我们的方法定位为基于非脂质的基于基于基因的精确药物目录的基因治疗开发的典范，从而填补了当前医学当前景观的显着空白。[5] [5] [5] [5] [5]。在弗朗西斯教授的经验丰富的领导下，我们的跨学科团队结合了高级技能，以支持治疗产品开发，确保知识产权（IP）保护和未来的翻译分析，并在2025年投资DPFS资金。