Jensen Melanie P, Barker Roger A
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Cambridge Stem Cell Institute, Cambridge, UK.
J Huntingtons Dis. 2019;8(1):9-22. doi: 10.3233/JHD-180320.
To date, no candidate intervention has demonstrated a disease-modifying effect in Huntington's disease, despite promising results in preclinical studies. In this commentary we discuss disease-modifying therapies that have been trialled in Huntington's disease and speculate that these failures may be attributed, in part, to the assumption that a single drug selectively targeting one aspect of disease pathology will be universally effective, regardless of disease stage or "subtype". We therefore propose an alternative approach for effective disease-modification that uses 1) a combination approach rather than monotherapy, and 2) targets the disease process early on - before it is clinically manifest. Finally, we will consider whether this change in approach that we propose will be relevant in the future given the recent shift to targeting more proximal disease processes-e.g., huntingtin gene expression; a timely question given Roche's recent decision to take on the clinical development of a promising new drug candidate in Huntington's disease, IONIS-HTTRx.
迄今为止，尽管临床前研究取得了令人鼓舞的结果，但尚无候选干预措施在亨廷顿舞蹈病中显示出疾病修饰作用。在这篇评论中，我们讨论了已在亨廷顿舞蹈病中进行试验的疾病修饰疗法，并推测这些失败可能部分归因于这样一种假设，即无论疾病阶段或“亚型”如何，单一药物选择性地针对疾病病理的一个方面将具有普遍疗效。因此，我们提出了一种有效的疾病修饰替代方法，即1）采用联合治疗而非单一疗法，以及2）在疾病临床显现之前尽早针对疾病进程。最后，鉴于最近转向针对更接近疾病进程的靶点，例如亨廷顿蛋白基因表达，我们将考虑我们提出的这种方法的改变在未来是否适用；鉴于罗氏公司最近决定承担一种有前景的亨廷顿舞蹈病新药候选药物IONIS-HTTRx的临床开发，这是一个适时的问题。
