Next-Generation Sensing For Human In Vivo Pharmacology- Accelerating Drug Development In Inflammatory Diseases

下一代人体药理学传感 - 加速炎症性疾病的药物开发

• 批准号: EP/S025987/1
• 负责人: Kev Dhaliwal
• 金额: $ 186.52万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FS025987%2F1
• 关键词: Next; Generation; Sensing; Human; Vivo

Inflammatory diseases are responsible for significant death, disability and poor outcomes and are a major financial burden on the health service. Despite decades of research and billions of pounds of R&D investment, no targeted therapeutics exist that modulate neutrophils (a key cell involved in inflammation and also the major cell that surrounds lung cancers and promotes invasiveness and poor prognosis). Acute and chronic inflammatory diseases such as asthma, COPD and lung injury are common and are now increasing in incidence and severity due to the aging population. Hence, this research addresses, one of the biggest challenges facing modern drug development, the need to develop in-human assay systems that provide confidence in early trials to either continue progressing or terminating drug development programmes. A major cause for failures of drug development include the historical reliance on animal models of disease which do not accurately reflect human disease. It is essential to develop new technologies to understand and evaluate disease and drug effectiveness in vivo in situ in humans.This research proposal will develop to near-clinical readiness, novel state of the art engineering and mathematical approaches to improve the quality of the data received from a sensing system called Kronoscan which is able to image and sense in real-time at microscopic detail in new dimensions using some of the world's fastest detector technology, measuring fluorescence lifetime data of inflammatory biomarkers at video rate (>10fps). Fluorescence lifetime overcomes the significant limitations of intensity fluorescence imaging and improves quantification. In patients, we will enable this through a method called microendoscopy suited to diseases that affect the lungs and gastrointestinal tracts and other areas where we can pass small imaging fibres deep into tissue. This method will be coupled alongside chemical SmartProbes which "light" up when they interact with inflamed cells and tissues.The project will be undertaken in partnership with GlaxoSmithKline who will provide "tool" compounds in development for clinical trials. GSK already use other imaging methods such as CT Scans and PET Imaging but see this approach of adding in high resolution ultra sensitive microscopic imaging to the evaluation of drug action as a major addition to the drug development process and an essential step to improving a currently expensive and poorly productive drug development pathway.Work on the different elements needed to create this technology platform will be undertaken by investigators spanning signal processing, electrical engineering, chemistry and clinical science at the University of Edinburgh in collaboration with GSK divisions. This project will be based in the Proteus interdisciplinary "hub" to ensure rapid product development. The researchers will spend time in each others labs in Edinburgh and GSK as well as arranging an open network meeting to ensure broader engagement. The scientists (researcher co-investigators) in the proposal will benefit significantly from networking and establishing the area of next-generation in vivo pharmacology. A key ambition of the research will be to pave the way for subsequent clinical and commercial impact and as such user (clinical and regulatory) input will be paramount during the development of the technology. The team will leverage existing capability and expertise in manufacturing, regulatory and commercialisation support to expedite development. In summary, this project will generate; 1) A cutting edge point-of-care technology platform which will help drug developers, patients, doctors and health care workers throughout the world. 2) Career development of the researcher Co-Is. 3) Develop an entirely new theme with "Big Pharma". 4) A sustainable network to disseminate the technology through GSK's imaging franchise.

炎症性疾病导致大量死亡、残疾和不良结果，并且是卫生服务的主要经济负担。尽管进行了数十年的研究和数十亿英镑的研发投资，但尚不存在调节中性粒细胞（参与炎症的关键细胞，也是肺癌周围并促进侵袭性和不良预后的主要细胞）的靶向疗法。哮喘、慢性阻塞性肺病和肺损伤等急性和慢性炎症性疾病很常见，并且由于人口老龄化，其发病率和严重程度正在增加。因此，这项研究解决了现代药物开发面临的最大挑战之一，即需要开发人体检测系统，为早期试验提供信心，以继续推进或终止药物开发计划。药物开发失败的一个主要原因包括历史上对动物疾病模型的依赖，而这些模型不能准确反映人类疾病。开发新技术来了解和评估人类体内疾病和药物的有效性至关重要。这项研究计划将发展为接近临床准备、新颖的最先进的工程和数学方法，以提高从称为 Kronoscan 的传感系统接收到的数据的质量，该系统能够使用一些世界上最快的探测器技术在新维度上实时成像和传感微观细节，测量荧光寿命数据 视频速率 (>10fps) 的炎症生物标志物。荧光寿命克服了强度荧光成像的显着限制并提高了定量性。对于患者，我们将通过一种称为显微内窥镜检查的方法来实现这一点，该方法适用于影响肺部和胃肠道以及我们可以将小型成像纤维深入组织的其他区域的疾病。该方法将与化学智能探针结合使用，当它们与发炎的细胞和组织相互作用时，智能探针会“发光”。该项目将与葛兰素史克合作进行，葛兰素史克将为临床试验提供正在开发的“工具”化合物。 GSK 已经使用其他成像方法，例如 CT 扫描和 PET 成像，但认为这种在药物作用评估中添加高分辨率超灵敏显微成像的方法是药物开发过程的主要补充，也是改善目前昂贵且生产力低下的药物开发途径的重要步骤。创建该技术平台所需的不同要素将由伦敦大学信号处理、电气工程、化学和临床科学领域的研究人员负责 爱丁堡与 GSK 部门合作。该项目将设在 Proteus 跨学科“中心”，以确保产品的快速开发。研究人员将在爱丁堡和葛兰素史克的彼此实验室共度时光，并安排一次开放网络会议，以确保更广泛的参与。该提案中的科学家（研究人员共同研究员）将从网络和建立下一代体内药理学领域中受益匪浅。该研究的一个主要目标是为后续的临床和商业影响铺平道路，因此用户（临床和监管）的输入在技术开发过程中将至关重要。该团队将利用制造、监管和商业化支持方面的现有能力和专业知识来加快开发。总之，该项目将产生； 1) 尖端的现场护理技术平台，将为世界各地的药物开发商、患者、医生和卫生保健工作者提供帮助。 2）研究员Co-Is的职业发展。 3）与“Big Pharma”一起开发一个全新的主题。 4) 一个可持续的网络，通过 GSK 的成像专营权传播技术。

项目成果

Specific in situ immuno-imaging of pulmonary-resident memory lymphocytes in human lungs.

• DOI: 10.3389/fimmu.2023.1100161
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Humphries, Duncan C.;O'Connor, Richard A.;Stewart, Hazel L.;Quinn, Tom M.;Gaughan, Erin E.;Mills, Beth;Williams, Gareth O. S.;Stone, James M.;Finlayson, Keith;Chabaud-Riou, Martine;Boudet, Florence;Dhaliwal, Kevin;Pavot, Vincent
• 通讯作者: Pavot, Vincent

Selective plane illumination optical endomicroscopy with polymer imaging fibers

使用聚合物成像光纤的选择性平面照明光学内显微镜

• DOI: 10.1063/5.0130486
• 发表时间: 2023
• 期刊: APL Photonics
• 影响因子: 5.6
• 作者: Roldán-Varona P

Solitary pulmonary nodule imaging approaches and the role of optical fibre-based technologies.

• DOI: 10.1183/13993003.02537-2020
• 发表时间: 2021-03
• 期刊: The European respiratory journal
• 作者: Fernandes S;Williams G;Williams E;Ehrlich K;Stone J;Finlayson N;Bradley M;Thomson RR;Akram AR;Dhaliwal K
• 通讯作者: Dhaliwal K

Pulmonary-Resident Memory Lymphocytes: Pivotal Orchestrators of Local Immunity Against Respiratory Infections.

• DOI: 10.3389/fimmu.2021.738955
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Humphries DC;O'Connor RA;Larocque D;Chabaud-Riou M;Dhaliwal K;Pavot V
• 通讯作者: Pavot V

Fibroblast Activation Protein Specific Optical Imaging in Non-Small Cell Lung Cancer.

• DOI: 10.3389/fonc.2022.834350
• 发表时间: 2022
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Mathieson L;O'Connor RA;Stewart H;Shaw P;Dhaliwal K;Williams GOS;Megia-Fernandez A;Akram AR
• 通讯作者: Akram AR