GlioPrevent: PiezoMagnetic Nanoparticles to Prevent Glioma Invasion in Human Brain Organoids

GlioPrevent：压电磁性纳米颗粒可预防人脑类器官中的神经胶质瘤侵袭

• 批准号: EP/Y00289X/1
• 负责人: ARATHYRAM RAMACHANDRA KURUP SASIKALA
• 金额: $ 20.63万
• 依托单位: University of Bradford
• 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=EP%2FY00289X%2F1
• 关键词: GlioPrevent; PiezoMagnetic; Nanoparticles; Prevent; Glioma

Glioblastoma multiforme (GBM) is the most common malignant brain tumour in the UK, accounting for more than one in every five brain tumour diagnoses. GBM patients have a poor prognosis, with just 20% surviving more than a year and 3% surviving more than three years. GBM tumours spread quickly, with aggressive finger-like growth into important brain locations. This makes treatment challenging, with GBM tumours notoriously difficult to remove surgically. Because of this, only easily accessible cancers are removed during surgery, and radiation and chemotherapy are delivered immediately after surgery to suppress tumour growth. Hence developing a more effective therapy for GBM, that can stop the growth/invasion of finger-like GBM cells into normal brain areas is needed. Researchers have been looking for a simple way to fix DNA mistakes to treat diseases ever since they learned that DNA changes cause cancer. A recent game-changer in this field is the CRISPR gene editing system. CRISPR can be used to cut the disease-causing genes, changing them in a way that can't be reversed by cell repair systems. This makes the cell more susceptible to therapeutic agents. Unfortunately, CRISPR has some limitations that restrict its use as a novel therapeutic. 1) The most common way to get CRISPR components into cells is with a modified virus, which can cause unwanted genetic changes, and 2) CRISPR may cut DNA outside of the intended genes and cause side effects (off-target editing). In this project we propose a novel delivery system (PiezoMagnetic nanoparticles, PMNPs) to overcome these problems and enable targeted delivery of CRISPR to systems modelling the human brain.PMNPs are materials that can be used to transport therapeutic agents into cells. The PMNPs are coated with the therapeutic agent, injected into the body and directed to the target cells using a magnet or ultrasound. In this work, we will produce a PMNP coated with a CRISPR system designed to target PLK1 and NeK 2 genes, which are associated with GBM. We believe preventing these genes from functioning will stop the growth of GBM cells, offering a potential avenue for future treatments. To increase the specificity of the PMNP to the GBM, a unique and clinically relevant targeting agent will also be applied to the carriers. These will be tested in small models of the human brain known as organoids. The treated PMNPs will be applied to models containing GBM and normal cells and the growth of the GBM cells will be measured over time. The results will lay the groundwork for the further development of PMNPs as a delivery system and organoids as a model testing system.The collaborators (the University of Bradford and University Hospital Dusseldorf) will also convene a panel of glioblastoma experts to advise on the research and to form the basis of a glioblastoma research network. The collaborators will work together to lead meetings and events to promote and drive forward further glioblastoma research.

胶质母细胞瘤多形（GBM）是英国最常见的恶性脑肿瘤，每五个脑肿瘤诊断中有超过一个。 GBM患者的预后较差，只有20％的人存活了一年以上，而3％的存活超过三年。 GBM肿瘤迅速扩散，具有侵略性的手指样生长到重要的大脑位置。这使得治疗具有挑战性，GBM肿瘤众所周知难以通过外科手术去除。因此，只有在手术期间清除了易于进入的癌症，并且在手术后立即进行放射和化学疗法以抑制肿瘤生长。因此，为GBM开发了更有效的疗法，可以阻止手指样GBM细胞的生长/侵袭到正常的大脑区域。研究人员一直在寻找一种简单的方法来解决DNA错误以治疗疾病，因为他们了解到DNA变化会导致癌症。 CRISPR基因编辑系统最近在该领域发生了改变游戏规则。 CRISPR可用于切割引起疾病的基因，以无法通过细胞修复系统逆转的方式改变它们。这使细胞更容易受到治疗剂的影响。不幸的是，CRISPR的局限性限制了其用作一种新型治疗。 1）将CRISPR成分进入细胞的最常见方法是使用修饰的病毒，这可能会导致不良的遗传变化，2）CRISPR可能会在预期基因之外切下DNA，并引起副作用（脱靶编辑）。在这个项目中，我们提出了一个新型的输送系统（Piezomagnetic Nanoparticles，PMNPS）来克服这些问题，并使有针对性的CRISPR靶向递送到对人脑建模的系统中。PMNPS是可用于将治疗剂传输到细胞中的材料。 PMNP涂有治疗剂，注射到体内，并使用磁铁或超声引导至靶细胞。在这项工作中，我们将生产一个带有CRISPR系统的PMNP，该系统旨在靶向与GBM相关的PLK1和NEK 2基因。我们认为，防止这些基因发挥作用将阻止GBM细胞的生长，从而为将来的治疗提供潜在的途径。为了提高PMNP对GBM的特异性，还将应用于载体。这些将在被称为类器官的人脑的小型模型中进行测试。处理后的PMNP将应用于包含GBM和正常细胞的模型，并且随着时间的推移将测量GBM细胞的生长。结果将为PMNP作为输送系统的进一步开发和器官作为模型测试系统的基础。合作者将共同领导会议和活动，以促进和推动进一步的胶质母细胞瘤研究。