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Sarah J Tabrizi, Scott Schobel, Emily C Gantman, Alexandra Mansbach, Beth Borowsky, Pavlina Konstantinova, Tiago A Mestre, Jennifer Panagoulias, Christopher A Ross, Maurice Zauderer, Ariana P Mullin, Klaus Romero, Sudhir Sivakumaran, Emily C Turner, Jeffrey D Long, Cristina Sampaio
UCL Huntington's Disease Centre, Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, UK Dementia Research Institute, University College London, UK.
Product Development Neuroscience, F Hoffmann-La Roche, Basel, Switzerland.
Lancet Neurol. 2022 Jul;21(7):632-644. doi: 10.1016/S1474-4422(22)00120-X.
The current research paradigm for Huntington's disease is based on participants with overt clinical phenotypes and does not address its pathophysiology nor the biomarker changes that can precede by decades the functional decline. We have generated a new research framework to standardise clinical research and enable interventional studies earlier in the disease course. The Huntington's Disease Integrated Staging System (HD-ISS) comprises a biological research definition and evidence-based staging centred on biological, clinical, and functional assessments. We used a formal consensus method that involved representatives from academia, industry, and non-profit organisations. The HD-ISS characterises individuals for research purposes from birth, starting at Stage 0 (ie, individuals with the Huntington's disease genetic mutation without any detectable pathological change) by using a genetic definition of Huntington's disease. Huntington's disease progression is then marked by measurable indicators of underlying pathophysiology (Stage 1), a detectable clinical phenotype (Stage 2), and then decline in function (Stage 3). Individuals can be precisely classified into stages based on thresholds of stage-specific landmark assessments. We also demonstrated the internal validity of this system. The adoption of the HD-ISS could facilitate the design of clinical trials targeting populations before clinical motor diagnosis and enable data standardisation across ongoing and future studies.
目前亨廷顿病的研究范式基于明显的临床表型的参与者，而没有涉及到它的病理生理学，也没有涉及到可以在功能下降前几十年发生的生物标志物变化。我们已经建立了一个新的研究框架，以标准化临床研究，并使干预研究更早地进行疾病过程。亨廷顿病综合分期系统（HD-ISS）包括一个生物学研究定义和基于生物学、临床和功能评估的循证分期。我们使用了一种正式的共识方法，涉及学术界、工业界和非营利组织的代表。HD-ISS 从出生开始就为研究目的对个体进行特征描述，从 0 期开始（即携带亨廷顿病基因突变但没有任何可检测到的病理变化的个体），使用亨廷顿病的遗传定义。然后，亨廷顿病的进展由潜在病理生理学的可测量指标（第 1 期）、可检测的临床表型（第 2 期）以及功能下降（第 3 期）来标记。个体可以根据特定阶段的标志性评估的阈值精确地分类到各个阶段。我们还证明了这个系统的内部有效性。HD-ISS 的采用可以促进针对临床运动诊断前人群的临床试验设计，并实现正在进行的和未来的研究的数据标准化。
