Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.
Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.
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DOI：
10.1007/s40120-023-00548-8
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发表时间：
2023-12
影响因子：
3.7
通讯作者：
Sabbagh, Marwan N.
中科院分区：
文献类型：
--
作者：
Sattler, Rita;Traynor, Bryan J.;Robertson, Janice;Van den Bosch, Ludo;Barmada, Sami J.;Svendsen, Clive N.;Disney, Matthew D.;Gendron, Tania F.;Wong, Philip C.;Turner, Martin R.;Boxer, Adam;Babu, Suma;Benatar, Michael;Kurnellas, Michael;Rohrer, Jonathan D.;Donnelly, Christopher J.;Bustos, Lynette M.;Van Keuren-Jensen, Kendall;Dacks, Penny A.;Sabbagh, Marwan N.
2023年3月在美国亚利桑那州斯科茨代尔举行的一次峰会聚焦于C9ORF72基因的内含子六核苷酸扩展及其与额颞痴呆(FTD)和肌萎缩侧索硬化症(ALS；C9ORF72-FTD/ALS)的相关性。此次峰会的目标是将基础科学家、临床研究人员、药物开发人员和受C9ORF72-FTD/ALS影响的个人联系起来，评估跨FTD-ALS疾病谱的协作努力如何打破现有的疾病孤岛。演讲和讨论涉及C9ORF72-FTD/ALS疾病机制的最新发现、疾病生物标记物的可用性和治疗开发的最新进展，以及针对受C9ORF72-FTD/ALS影响的个人和无症状病理扩展携带者的预防和治疗的临床试验设计。C9ORF72相关的六核苷酸重复序列扩增是ALS和FTD的重要基因座。C9ORF72-FTD/ALS的特征可能是C9ORF72蛋白功能丧失，二肽重复(DPR)蛋白和六核苷酸重复RNA均导致功能毒性获得。峰会讨论的C9ORF72-FTD/ALS治疗策略包括使用反义寡核苷酸、腺相关病毒(AAV)介导的基因沉默和基因传递，以及针对与C9ORF72扩张相关的RNA结构的工程小分子。神经丝轻链、DPR蛋白和反式反应(TAR)DNA结合蛋白43(TDP-43)相关的分子变化被提出为候选生物标记物。同样，测量结构、功能和代谢变化的脑成像方式(即磁共振成像[MRI]和正电子发射断层扫描[PET])被讨论为在症状前期和症状阶段监测受C9ORF72-FTD/ALS影响的个人的重要工具。最后，峰会与会者评估了目前可用于FTD或ALS患者的临床试验设计，并得出结论，与FTD/ALS患者相关的疗法，如那些专门针对C9ORF72的疗法，可能需要使用涵盖FTD和ALS临床症状的复合终点进行测试。后者将需要新的临床试验设计，以涵盖跨越FTD/ALS谱的所有患者亚组。网上版载有补充材料，可在10.1007/s40120-023-00548-8查阅。C9ORF72峰会于2023年3月在美国亚利桑那州斯科茨代尔举行。一些患有额颞叶痴呆或肌萎缩侧索硬化症的人，他们的一个基因发生了变化；这个基因的名字是C9ORF72。携带这种基因差异的人通常是从父母那里继承的。研究人员正在提高他们对C9ORF72基因变化如何影响人类的理解，并正在努力利用这一知识来开发肌萎缩侧索硬化症和额颞痴呆的治疗方法。除了研究C9ORF72突变如何导致细胞功能障碍、额颞部痴呆和肌萎缩侧索硬化症临床症状的细胞和分子机制外，研究界还致力于开发称为生物标记物的测量方法，以多种方式加强治疗开发工作。例如，监测疾病活动，识别那些有患肌萎缩侧索硬化症或额颞叶痴呆风险的人，预测哪些人可能从特定的治疗中受益，以及表明一种药物已经产生了生物效应。识别有患肌萎缩侧索硬化症或额颞叶痴呆风险的健康人的标记物可以用来测试在一个人出现任何症状之前就开始的治疗，希望能推迟甚至防止他们的发病。网上版载有补充材料，可在10.1007/s40120-023-00548-8查阅。
A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion in the C9ORF72 gene and its relevance in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this summit was to connect basic scientists, clinical researchers, drug developers, and individuals affected by C9ORF72-FTD/ALS to evaluate how collaborative efforts across the FTD-ALS disease spectrum might break down existing disease silos. Presentations and discussions covered recent discoveries in C9ORF72-FTD/ALS disease mechanisms, availability of disease biomarkers and recent advances in therapeutic development, and clinical trial design for prevention and treatment for individuals affected by C9ORF72-FTD/ALS and asymptomatic pathological expansion carriers. The C9ORF72-associated hexanucleotide repeat expansion is an important locus for both ALS and FTD. C9ORF72-FTD/ALS may be characterized by loss of function of the C9ORF72 protein and toxic gain of functions caused by both dipeptide repeat (DPR) proteins and hexanucleotide repeat RNA. C9ORF72-FTD/ALS therapeutic strategies discussed at the summit included the use of antisense oligonucleotides, adeno-associated virus (AAV)-mediated gene silencing and gene delivery, and engineered small molecules targeting RNA structures associated with the C9ORF72 expansion. Neurofilament light chain, DPR proteins, and transactive response (TAR) DNA-binding protein 43 (TDP-43)–associated molecular changes were presented as biomarker candidates. Similarly, brain imaging modalities (i.e., magnetic resonance imaging [MRI] and positron emission tomography [PET]) measuring structural, functional, and metabolic changes were discussed as important tools to monitor individuals affected with C9ORF72-FTD/ALS, at both pre-symptomatic and symptomatic disease stages. Finally, summit attendees evaluated current clinical trial designs available for FTD or ALS patients and concluded that therapeutics relevant to FTD/ALS patients, such as those specifically targeting C9ORF72, may need to be tested with composite endpoints covering clinical symptoms of both FTD and ALS. The latter will require novel clinical trial designs to be inclusive of all patient subgroups spanning the FTD/ALS spectrum. The online version contains supplementary material available at 10.1007/s40120-023-00548-8. The C9ORF72 Summit was held in March 2023 in Scottsdale, Arizona (USA). Some people who have the disease frontotemporal dementia or the disease amyotrophic lateral sclerosis have a change in one of their genes; the name of the gene is C9ORF72. People who carry this genetic difference usually inherited it from a parent. Researchers are improving their understanding of how the change in the C9ORF72 gene affects people, and efforts are being made to use this knowledge to develop treatments for amyotrophic lateral sclerosis and frontotemporal dementia. In addition to studying the cellular and molecular mechanisms of how the C9ORF72 mutation leads to cellular dysfunction and frontotemporal dementia and amyotrophic lateral sclerosis clinical symptoms, a large effort of the research community is aimed at developing measurements, called biomarkers, that could enhance therapy development efforts in multiple ways. Examples include monitoring of disease activity, identifying those at risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, predicting which people might benefit from a particular treatment, and showing that a drug has had a biological effect. Markers that identify healthy people who are at risk of developing amyotrophic lateral sclerosis or frontotemporal dementia could be used to test treatments that would start before a person shows any symptoms and hopefully would delay or even prevent their onset. The online version contains supplementary material available at 10.1007/s40120-023-00548-8.
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