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Identification of therapeutic targets in C9orf72-linked FTD and MND

C9orf72 相关 FTD 和 MND 治疗靶点的鉴定

基本信息

批准号：
MR/W00416X/1
负责人：
Guillaume Hautbergue
金额：
$ 20.12万
依托单位：
University of Sheffield
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW00416X%2F1
关键词：
Identification therapeutic targets C9orf72 linked

项目摘要

Motor Neuron Disease (MND) is a devastating and incurable adult-onset motor disorder. It affects the neurons controlling muscle movement, thus causing muscle weakness and degeneration, leading to paralysis and death by respiratory failure. The most common genetic cause of MND is a mutation in the gene C9orf72. Interestingly, mutations in this gene are also the most frequent cause of frontotemporal dementia (FTD), which, in turns, affects neurons involved in higher functions, such as language and behaviour.Although the two pathologies share the same genetic cause, they trigger two different diseases that in some patients progress from one to the other. The factors involved in the development of one or the other disorder are still unknown and this is a significant challenge for the identification of therapeutic targets. In addition, in vitro and in vivo models used in the laboratory to study disease mechanisms and identify therapeutic targets rely on the expression of the mutant gene C9orf72, which is common to both disorders. The challenge is, therefore, to understand more in depth the underlying pathological consequences of the mutation in the cells affected by the disease, both neurons and surrounding non-neuronal cells and then model them accordingly. This may then provide the opportunity to identifying key points of intervention to alter these ongoing disease mechanisms and design therapeutics for specific patient benefit. Gaining this human biological insight and constructing models to test the biological hypotheses is a key challenge for companies such as Cerevance in their identification of new targets for the design of truly novel therapeutics for neurodegenerative disease.To solve this challenge, Dr Ferraiuolo's team at the Sheffield Institute for Translational Neuroscience (SITraN) and Cerevance have come together to share complementary expertise and technologies. Dr Ferraiuolo has developed an in vitro model that recapitulates important and distinct aspects of the two neurodegenerative diseases and, therefore, it is likely to be a suitable model for target validation and drug discovery. Cerevance has optimised cutting-edge NETSseq (Nuclear Enriched Transcript Sort sequencing) technology to unravel disease mechanisms and developed novel drug development strategies.The consortium between Dr Ferraiuolo at SITraN and Cerevance aims to 1. Perform deep transcriptomic on cortical and spinal tissue of glia and neurons from C9orf72 MND & FTD patients and controls to identify the presence of different physiological and pathological pathways occurring in the areas that are affected or spared in the 2 diseases.2. Perform deep transcriptomic on in vitro induced astrocytes and cortical and motor neurons from C9orf72 MND & FTD patients and controls to assess the presence of the pathways identified in post-mortem tissues3. Apply bioinformatic analysis of said datasets showing impact of disease on individual cell types and network function / dysfunction4. Validate potential therapeutic targets by suppressing or overexpressing specific molecules in the human derived cellular systems 5. Test drugs for potential therapeutic targets.To accomplish these aims, Dr Myszczynska, who has recently completed her PhD training and is currently a post-doctoral researcher in Dr Ferraiuolo's team, will spend 2 years at Cerevance. Dr Myszczynska will receive world-class training in novel approaches for drug development and NETSseq, a cutting edge technique for deep transcriptomics of complex tissues. In turn, she will support Cerevance with her expertise acquired in over 6 years at SITraN in the field of MND and FTD, in vitro disease modelling using patient-derived cells and bioinformatics. In conclusion the knowledge exchange between Cerevance and SITraN through the secondment of Dr Myszczynska, will not only answer important biological questions, but will also bridge knowledge gaps in the academic and industrial sectors.

运动神经元病（MND）是一种毁灭性的和不可治愈的成人发病的运动障碍。它会影响控制肌肉运动的神经元，从而导致肌肉无力和退化，导致瘫痪和呼吸衰竭死亡。MND最常见的遗传原因是基因C9 orf 72的突变。有趣的是，该基因的突变也是额颞叶痴呆（FTD）最常见的原因，而后者又会影响到涉及更高功能的神经元，如语言和行为。尽管这两种病理具有相同的遗传原因，但它们会引发两种不同的疾病，在某些患者中会从一种发展到另一种。参与一种或另一种疾病发展的因素仍然未知，这对确定治疗靶点是一个重大挑战。此外，在实验室中用于研究疾病机制和确定治疗靶点的体外和体内模型依赖于突变基因C9 orf 72的表达，这是两种疾病所共有的。因此，挑战在于更深入地了解受疾病影响的细胞（神经元和周围的非神经元细胞）突变的潜在病理后果，然后相应地对其进行建模。然后，这可以提供机会来确定干预的关键点，以改变这些正在进行的疾病机制，并为特定的患者利益设计治疗方法。对于Cerevance这样的公司来说，获得这种人类生物学洞察力并构建模型来测试生物学假设是一个关键挑战，因为他们要确定新的靶点，以设计真正新颖的神经退行性疾病疗法。为了解决这一挑战，谢菲尔德转化神经科学研究所（SITraN）和Cerevance的Ferraiuolo博士团队走到一起，分享互补的专业知识和技术。Ferraiuolo博士开发了一种体外模型，概括了这两种神经退行性疾病的重要和不同方面，因此，它可能是靶点验证和药物发现的合适模型。Cerevance优化了尖端的NETSseq（核富集转录排序）技术，以揭示疾病机制，并开发了新药开发策略。SITraN的Ferraiuolo博士和Cerevance的联盟旨在1.对来自C9 orf 72 MND & FTD患者和对照的神经胶质和神经元的皮质和脊髓组织进行深度转录组学，以鉴定在这2种疾病中受影响或未受影响的区域中发生的不同生理和病理通路的存在。对来自C9 orf 72 MND & FTD患者和对照的体外诱导星形胶质细胞以及皮质和运动神经元进行深度转录组学分析，以评估在死后组织中鉴定的通路的存在3。应用所述数据集的生物信息学分析，显示疾病对个体细胞类型和网络功能/功能障碍的影响4。通过抑制或过表达人源性细胞系统中的特定分子来抑制潜在的治疗靶点5。测试药物的潜在治疗靶点。为了实现这些目标，Myszczynska博士最近完成了博士培训，目前是Ferraiuolo博士团队的博士后研究员，她将在Cerevance工作2年。Myszczynska博士将接受世界一流的药物开发新方法和NETSseq培训，NETSseq是复杂组织深层转录组学的尖端技术。反过来，她将利用她在SITraN 6年多来在MND和FTD领域获得的专业知识，使用患者源性细胞和生物信息学进行体外疾病建模，为Cerevance提供支持。总之，Cerevance和SITraN之间通过Myszczynska博士的借调进行的知识交流不仅将回答重要的生物学问题，而且还将弥合学术和工业部门的知识差距。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons.

DOI：
10.26508/lsa.202101276
发表时间：
2022-09
期刊：
LIFE SCIENCE ALLIANCE
影响因子：
4.4
作者：
Marchi, Paolo M.;Marrone, Lara;Brasseur, Laurent;Coens, Audrey;Webster, Christopher P.;Bousset, Luc;Destro, Marco;Smith, Emma F.;Walther, Christa G.;Alfred, Victor;Marroccella, Raffaele;Graves, Emily J.;Robinson, Darren;Shaw, Allan C.;Wan, Lai Mei;Grierson, Andrew J.;Ebbens, Stephen J.;De Vos, Kurt J.;Hautbergue, Guillaume M.;Ferraiuolo, Laura;Melki, Ronald;Azzouz, Mimoun
通讯作者：
Azzouz, Mimoun

DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity.