Greig Cephalopolysyndactyly Syndrome

The news that your child has a health issue is unwelcome news to any parent, but the diagnosis of a rare disease brings a unique, complex set of challenges, and initiates a life-long journey of answer-seeking. As I awaited the birth of my son, instead of prepping the nursery, I was instead informed that he was likely to be born with a rare condition that could severely impact his quality of life. An MRI in the first hours of his life had shown he suffered two strokes in utero, and led physicians to a likely diagnosis of Greig syndrome, a rare genetic disease defined by skeletal deficiencies. Having a rare disease, or being the family of a loved one with rare disease, can be a lonely feeling with much uncertainty about the future. There is often little literature on the condition, few advocacy groups, and limited or no treatment options or clinical trials for investigational treatments. But, when examined together, rare disease patients are anything but rare, and they are anything but alone. According to the National Institutes of Health (NIH), 30 million Americans, or 10 percent of the population, have a rare disease. When you look across the globe, 3.5-5.9% of the world’s population, or 263-446 million people, have a rare disease. This Rare Disease Day is an opportunity to raise awareness of the challenges those living with a rare disease face, and why there’s reason to hope, thanks to advances in science that could potentially change the lives of millions of patients. The rare disease gap From diagnosis to treatment, the lifecycle of a rare disease is typically defined by more questions than answers. These questions started before my son was even born. Upon discovering he had extra toes on a late-stage ultrasound along with several abnormalities in his brain, diagnoses of trisomy 18, and rare diseases such as Dandy Walker syndrome and Greig syndrome were being discussed, as my husband and I scrambled to get a clear definition of these conditions and what they would mean for my son’s life – one more devastating than the next. The lack of research in rare disease and variances in symptoms makes it difficult for providers to make an informed diagnosis, which can take years. Even as someone who has spent their career in central nervous system (CNS) disorders, working in close quarters with neurologists and neurosurgeons and well-versed in complex medical speak, I was often at a loss of what the next steps of care held for my son, and I questioned every symptom in those early months of life. Once a diagnosis is made, the assurance of an answer can be short lived – the path toward sustainable disease management and treatment varies widely by disease. There are approximately 7,000 rare diseases, and yet, only 5% have approved drugs. This presents a Catch-22 – the lack of precedent means rare diseases often do not have a clearly defined clinical trial roadmap or established endpoints, making scientific advancements difficult. The inherently small patient populations also make it difficult for researchers to devote resources to and implement a drug development program and conduct clinical trials. When research is pursued, developing rare disease treatments is a challenge due to their complex biology. Without treatment, patients and their families often need to manage these conditions with supportive care, such as a strict diet in the case of metabolic disorders. The hope in mRNA medicine Rare disease is often viewed as a forgotten, nonlucrative area of research. But, when companies put their valuable resources toward researching your disease that seems to only have dead-ends, it can feel like a sigh of relief – someone cares. Even if it doesn’t lead to solutions, knowing someone is trying can make a world of a difference, and ease the heavy uncertainty patients and their families operate under every day. While mRNA became widely known during the pandemic because of its use in Covid-19 vaccines, the technology was investigated as a therapeutic long before then, and has particular potential for rare diseases. mRNA is a molecule that contains instructions that direct the cells to make proteins. Because many rare diseases are caused by a missing or dysfunctional protein, mRNA could help patients with rare metabolic disorders and potentially a variety of these protein and enzyme deficiencies. Now, scientists are investigating mRNA therapeutic candidates, and are seeing promising results to date. One of the biggest benefits to mRNA technology is its flexibility, allowing for slight variations to successfully target adjacent diseases. Advancing the fight against rare disease Despite needing a life-saving shunt to treat hydrocephalus in his first few months of life and multiple orthopedic surgeries in the years to follow, I am grateful that my fifteen-year-old son has largely lived a normal life with only small limitations. He’s one of the lucky ones. There are millions of families just like mine, waiting for the smoke to clear and for long-awaited answers. Pursuing research in rare disease requires researchers to think differently about R&D, commit to a deep understanding of a patient’s lived experience, and build close relationships with the rare disease community. Our family motto is “never give up, never surrender.” Every rare disease patient is a warrior, but the fight doesn’t need to fought alone, and we’re grateful for the dedication to innovative, collaborative research that advances the battle.

在一项新的研究中，Treutlein和她的同事们如今在不同的时间点和非常详细地研究了人类大脑类器官内的数千个细胞。他们成功地将这些数据表示为一种图谱，用于显示这种大脑类器官内每个细胞的分子指纹。 人类的大脑很可能是整个生物世界中最复杂的器官，长期以来一直是科学家们着迷的对象。然而，研究大脑，特别是调节和指导它的发育的基因和分子开关，并不是一件容易的事。 迄今为止，科学家们一直在使用动物模型（主要是小鼠）进行研究，但他们的发现不能直接适用于人类。小鼠的大脑结构与人类不同，缺乏人类大脑典型的皱褶表面。迄今为止，细胞培养物在这一领域的价值有限，因为细胞在培养皿上生长时往往会扩散到大片区域；这与大脑的自然三维结构不相符。 绘制分子指纹图谱 瑞士苏黎世联邦理工学院生物系统科学与工程系的Barbara Treutlein教授及其团队采取了一种新的方法来研究人类大脑的发育：他们正在培养和使用类器官---毫米大小的可以利用所谓的多能性干细胞培育出的三维组织。 只要这些多能性干细胞接受到正确的刺激，他们就能将它们编程成为身体中存在的任何一种细胞，包括神经元。当它们聚集成一个小的组织球，然后暴露在适当的刺激下，它们甚至可以自我组装，形成具有复杂组织结构的三维大脑类器官。 在一项新的研究中，Treutlein和她的同事们如今在不同的时间点和非常详细地研究了人类大脑类器官内的数千个细胞。他们的目标是用分子遗传学术语来描述这些细胞：换句话说，所有基因转录本（转录组）的总量作为基因表达的衡量标准，同时基因组可访问性作为调节活性的衡量标准。他们成功地将这些数据表示为一种图谱，用于显示这种大脑类器官内每个细胞的分子指纹。相关研究结果于2022年10月5日在线发表在Nature期刊上，论文标题为“Inferring and perturbing cell fate regulomes in human brain organoids”。 然而，这个过程产生了巨大的数据集：这种大脑类器官中的每个细胞有2万个基因，而每个大脑类器官又由成千上万个细胞组成。论文共同第一作者、Treutlein团队的博士生Jonas Fleck解释说，“这导致了一个巨大的矩阵，而我们能够解决它的唯一方法是借助合适的程序和机器学习。” 为了分析所有这些数据并预测基因调节机制，这些作者开发了他们自己的程序。Fleck说，“我们可以用它来为每个基因生成一个完整的相互作用网络，并预测当该基因失效时在真实的细胞中会发生什么。” 识别基因开关 这项新研究的目的是系统地确定那些对大脑器官不同区域的神经元发育有重大影响的基因开关。在CRISPR-Cas9系统的帮助下，这些作者有选择地关闭了每个细胞中的一个基因，在整个大脑类器官中同时关闭了大约二十多个基因。这使他们能够发现各自的基因在大脑类器官的发育中发挥了什么作用。 论文共同第一作者、Treutlein团队博士生Sophie Jansen解释说，“这项技术可用于筛选参与疾病的基因。此外，我们还可以看看这些基因对大脑类器官内不同细胞的发育所产生的影响。” 检查前脑中的模式形成 为了检验他们的理论，这些作者选择了GLI3基因作为例子。该基因编码的转录因子GLI3可停靠在DNA上的某些位点，以调节另一个基因。当GLI3被关闭时，细胞中的分子机制被阻止读取该基因并将它转录为RNA分子。 在小鼠中，GLI3基因的突变可导致中枢神经系统畸形。它在人类神经元发育中的作用以前没有被探索过，但人们知道，该基因的突变会导致格雷格头-多指-并指综合征（Greig cephalopolysyndactyly syndrome）和帕利斯特-霍尔综合征（Pallister Hall Syndrome）等疾病。 大脑类器官发育的多组学图谱揭示了发育的层次和命运决定的关键阶段。图片来自Nature, 2022, doi:10.1038/s41586-022-05279-8。 沉默这个GLI3基因使得这些作者既能验证他们的理论预测，又能在细胞培养物中直接确定这个基因的缺失如何影响大脑类器官的进一步发育。Treutlein说，“我们首次发现，GLI3基因参与了人类前脑模式的形成。这在以前只在小鼠身上发现过。” 模型系统反映了发育生物学 她解释说，“这项新研究令人兴奋的是，它可以让你使用来自这么多个细胞的全基因组数据来推测单个基因发挥什么作用。在我看来，同样令人兴奋的是，这些在培养皿中制作的模型系统确实反映了我们从小鼠身上了解到的发育生物学。” Treutlein还发现了一个有趣的现象，即这种培养基如何产生具有与人类大脑结构相似的自组装组织——不仅在形态学水平上，而且（正如这些作者在这项新的研究中所展示的那样）在基因调控和模式形成水平上。她指出，“像这样的类器官确实是研究人类发育生物学的一种极好的方法。” 多用途的大脑类器官 对由人类细胞材料组成的类器官的研究有一个优势，即所获得的研究结果可以适用于人类身上。它们不仅可以用来研究基本的发育生物学，还可以研究基因在疾病或大脑发育障碍中的作用。例如，Treutlein和她的同事们正在用这种类型的类器官研究自闭症和异位（heterotopia）的遗传原因；在异位中，神经元出现在大脑皮层的正常解剖位置之外。 类器官也可用于测试药物，并可能用于培养可移植的器官或器官部分。Treutlein证实，制药行业对这些细胞培养物非常感兴趣。 然而，培养类器官需要时间和精力。此外，每个细胞团都是单独发育的，而不是以标准化的方式发育。这就是为何Treutlein和她的团队正在努力改进类器官并使得它们的制造过程自动化。（生物谷 Bioon.com） 参考资料： 1. Jonas Simon Fleck et al. Inferring and perturbing cell fate regulomes in human brain organoids. Nature, 2022, doi:10.1038/s41586-022-05279-8. 2. Mapping human brain developmenthttps://medicalxpress.com/news/2022-10-human-brain.html