INfLUENCE-HD: Influencing juvenile-onset Huntington's disease monitoring with remote Neurofilament light quantification

亨廷顿病(HD)是一种罕见的遗传性疾病，会导致大脑退化，是最常见的遗传性痴呆之一。每一例HD都是由亨廷顿蛋白基因的突变引起的，这种突变会导致细胞产生一种对脑细胞有毒的有害蛋白质。通常情况下，HD表现在30-50岁的成年期。然而，更严重的突变会导致症状出现得更早。少年型亨廷顿病(JoHD)是指在21岁之前开始出现HD症状。JoHD是一种极端的疾病，很难进行全面的研究，这意味着它还不被很好地理解，我们进行JoHD临床试验的能力也是有限的。我之前曾报告过第一次反映成人发病HD进展的血液测试，包括临床症状的恶化和脑扫描测量的脑萎缩。这项测试测量了一种名为神经丝光(NFL)的大脑蛋白质，脑脊液(CSF-环绕大脑和脊髓的液体)和血液(由于超灵敏的测量技术现在可以检测到)中的水平告诉我们脑细胞的健康状况。在少数JoHD患者中，我发现血液NFL比健康儿童高得多。我现在正在努力获得在JoHD患者中实施临床试验所需的急需信息。最终，我们需要强大而敏感的工具，称为生物标记物，可以告诉我们一种药物是否有效。然而，严重的JoHD使这些年轻患者很难进入临床并参与研究。如果我们能从遥远的地方研究JoHD，那么我们就可以收集足够的数据来更好地了解这种疾病。我已经开发出一种方法，通过手指刺痛采集血液，以测量患者的NFL，这些患者可以在自己的家里参与这项研究。我希望这将增加我们可以研究的JoHD患者的吸收，并使我能够产生这些被忽视的患者中最大的队列。我是Join-HD的全球首席研究员，这是JoHD的第一个全球注册研究。我将使用注册中心招募多达100名JoHD患者，为两年内每6个月重复进行一次NFL测量提供血液。INfLUENCE-HD包括一项重大合作努力，使用来自现有人类研究的样本，包括儿童和年轻人，一直到具有HD基因的老年人。我将研究这些样本中的NFL，以生成一个模型，说明NFL在HD突变携带者的一生中是如何变化的。我将包括来自大脑扫描的数据，以加强这些模型，并提供更详细的NFL变化背后的疾病生物学信息。通过利用多个合作者提供的现有人类，这项工作可以快速高效地进行，这项工作将显著而有效地促进NFL在帮助理解JoHD、预测其临床进程和加速药物开发方面的作用。此外，NFL的家庭测试可能会影响其他神经退行性疾病，并改变神经学内部监测患者疾病的方式。作为HD药物开发方面与主要制药行业参与者的合作者，以及关键路径研究所的顾问，关键路径研究所反过来为政府药品监管机构提供建议，我处于推动这项工作向前发展的理想位置，以促进为这种毁灭性疾病和其他疾病开发新的治疗方法。

Huntington's disease (HD) is a rare inherited disease that causes brain degeneration and is one of the most common inherited dementias. Every case of HD is caused by a mutation in the huntingtin gene that causes cells to produce a harmful protein that is toxic to brain cells. Typically, HD manifests in adulthood between 30-50 years. However, more severe mutations cause symptoms to present earlier. Juvenile-onset Huntington's disease (JoHD) is when HD symptoms start before the age of 21. JoHD is ultrarare making it difficult to study fully, when means it is not well understood and our ability to run clinical trials for JoHD is limited.I have previously reported the first blood test that reflects adult-onset HD progression including the worsening of clinical symptoms and brain shrinkage measured by brain scans. This test measures a brain protein called Neurofilament light (NfL) of which levels in the cerebrospinal fluid (CSF - the fluid that surrounds the brain and spinal cord) and blood (now detectable due to ultrasensitive measurement techniques) tells us about the health of brain cells. In a small number of JoHD patients, I showed blood NfL was much higher than in healthy children.I am now working to gain the much-needed information required to implement clinical trials in JoHD patients. Ultimately, we need robust and sensitive tools called biomarkers that can tell us whether a drug is working. However, the severity of JoHD makes it hard for these young patients to make it to clinic and to take part in research. If we could study JoHD from afar then we could collect enough data to better understand the disease. I have developed a way to collect blood via a finger prick to measure NfL from patients who can take part in this research from their own homes. I hope this will increase the uptake of JoHD patients we can study and allow me to generate the largest cohort of these neglected patients. I am the global Chief Investigator of JOIN-HD, the first global registry study of JoHD. I will use the registry to recruit up to 100 JoHD patients to provide blood for repeated NfL measurements every 6 months over 2-years.INfLUENCE-HD includes a major collaborative effort to use samples from existing human studies including children and young adults, right up to older adults with the HD gene. I will study NfL in these samples to generate a model for how NfL changes throughout the life of a HD mutation carrier. I will include data from brain scans to strengthen these models and provide more detailed information of the disease biology underlying NfL changes. By using existing human supplied by several collaborators, this work can proceed quickly and efficiently.Together, this work will significantly and efficiently advance the role of NfL to help understand JoHD, predict its clinical course and accelerate the development of drugs. Further, home testing of NfL has potential of impacting other neurodegenerative conditions and transforming how patients' disease is monitored within Neurology. As a collaborator with the major pharmaceutical industry players in HD drug development, and an advisor to the Critical Path Institute, which in turn advises governmental drug regulatory agencies, I am ideally placed push this work forward to facilitate developing new treatments for this devastating illness and others.