Identification of therapeutic targets in C9orf72-linked FTD and MND

运动神经元病（MND）是一种毁灭性且无法治愈的成人运动障碍。它影响控制肌肉运动的神经元，从而引起肌肉无力和退化，导致瘫痪和呼吸衰竭死亡。MND最常见的遗传原因是C9orf72基因的突变。有趣的是，该基因的突变也是额颞叶痴呆（FTD）的最常见原因，而后者反过来又影响涉及语言和行为等高级功能的神经元。尽管这两种病症具有相同的遗传原因，但它们引发的两种不同的疾病在一些患者中会从一种疾病发展到另一种疾病。其中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C9orf72的表达，该基因在两种疾病中都很常见。因此，挑战在于更深入地了解受疾病影响的细胞（包括神经元和周围的非神经元细胞）突变的潜在病理后果，然后相应地对它们进行建模。这可能会为确定干预的关键点提供机会，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。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Cerevance等公司在确定新靶点以设计真正新颖的神经退行性疾病治疗方法时面临的关键挑战。为了解决这一挑战，谢菲尔德转化神经科学研究所（SITraN）的Ferraiuolo博士团队与Cerevance合作，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而独特的方面，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（核富集转录物排序测序）技术，以揭示疾病机制并开发新的药物开发策略。SITraN的Ferraiuolo博士和Cerevance的合作目标是：对C9orf72 MND和FTD患者和对照组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研究，以确定在两种疾病中受影响或未受影响的区域存在不同的生理和病理通路。对C9orf72 MND和FTD患者和对照组体外诱导的星形胶质细胞、皮质和运动神经元进行深度转录组学研究，以评估死后组织中发现的通路的存在3。对上述数据集进行生物信息学分析，显示疾病对个体细胞类型和网络功能/功能障碍的影响4。通过抑制或过度表达人源性细胞系统中的特定分子来验证潜在的治疗靶点。测试药物以寻找潜在的治疗靶点。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博士将在药物开发的新方法和NETSseq方面接受世界级的培训，NETSseq是复杂组织深层转录组学的前沿技术。反过来，她将利用她在SITraN工作6年多期间在MND和FTD领域获得的专业知识，利用患者来源的细胞和生物信息学进行体外疾病建模，为Cerevance提供支持。最后，通过借调Myszczynska博士，Cerevance和SITraN之间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。

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.