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.

多形性胶质母细胞瘤(GBM)是英国最常见的恶性脑瘤，占脑瘤诊断的五分之一以上。GBM患者预后较差，只有20%的患者存活一年以上，3%的患者存活三年以上。基底膜肿瘤扩散迅速，具有侵袭性的指状生长，进入重要的大脑部位。这使得治疗具有挑战性，众所周知，GBM肿瘤很难通过手术切除。正因为如此，在手术期间，只有容易接近的癌症才会被切除，手术后立即进行放射和化疗以抑制肿瘤的生长。因此，需要开发一种更有效的治疗基底膜的方法，以阻止指状基底膜细胞生长/侵袭正常脑区。自从了解到DNA变化会导致癌症以来，研究人员一直在寻找一种简单的方法来修复DNA错误，以治疗疾病。最近这一领域的游戏规则改变者是CRISPR基因编辑系统。CRISPR可以用来切割致病基因，以一种细胞修复系统无法逆转的方式改变它们。这使得细胞更容易受到治疗剂的影响。不幸的是，CRISPR有一些局限性，限制了它作为一种新的治疗方法的使用。1)将CRISPR组件导入细胞的最常见方法是使用修改后的病毒，这可能会导致不必要的基因变化；2)CRISPR可能会在预期基因之外切割DNA，并导致副作用(非靶标编辑)。在这个项目中，我们提出了一种新型的递送系统(压磁纳米颗粒，PMNPs)来克服这些问题，并使CRISPR能够定向递送到模拟人脑的系统中。PMNPs是一种可以用于将治疗剂输送到细胞中的材料。PMNPs被涂上治疗剂，注射到体内，并使用磁铁或超声波引导到目标细胞。在这项工作中，我们将生产一种包被CRISPR系统的PMNP，该系统旨在针对与GBM相关的PLK1和NEK 2基因。我们相信，阻止这些基因发挥作用将阻止GBM细胞的生长，为未来的治疗提供了一条潜在的途径。为了提高PMNP对GBM的特异性，还将对携带者应用一种独特的、具有临床意义的靶向试剂。这些将在被称为有机体的人类大脑的小模型中进行测试。经过处理的PMNPs将被应用于含有GBM和正常细胞的模型，并将随着时间的推移测量GBM细胞的生长。这些结果将为PMNPs作为递送系统和有机物作为模型测试系统的进一步开发奠定基础。合作者(布拉德福德大学和杜塞尔多夫大学医院)还将召集胶质母细胞瘤专家小组就研究提供建议，并形成胶质母细胞瘤研究网络的基础。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。