Centre de Recherche du CHU de Québec - Université Laval, Québec, QC G1V 4G2, Canada; Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC G1V 0A6, Canada.
Centre de Recherche du CHU de Québec - Université Laval, Québec, QC G1V 4G2, Canada; Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC G1V 0A6, Canada.
Neurobiol Dis. 2019 Dec;132:104569. doi: 10.1016/j.nbd.2019.104569. Epub 2019 Aug 6.
The types of treatments and interventions being developed for chronic neurodegenerative disorders have expanded considerably in recent years. In addition to the variety of targets being pursued, strategies have moved from symptom management to more directed disease-modifying approaches. Among them are antibody-based therapies, which are not only being evaluated for a range of tauopathies and synucleinopathies, but are also emerging as a potential application for monogenic disorders of the central nervous system (CNS), including Huntington's disease (HD). Despite the excitement around the early trial data of anti-sense oligonucleotides (ASO) treatment for such disorders, antibody therapies may hold the key to tackling another aspect of the disease that could be critical to its pathogenesis. While gene-based methodologies are designed to lower, predominantly within cellular elements, mutant huntingtin protein (mHtt) - the genetic product of HD - the pathological protein is abundant in free forms and in several compartments including the cerebrospinal fluid, the plasma and the extracellular matrix. With accumulating evidence for the spreading and seeding capacities of mHtt, it may indeed be essential to target the protein both intracellularly and extracellularly. Therefore, free forms of mHtt not only represents an ideal target for antibodies, but one that needs to be addressed if meaningful and maximal clinical benefits are to be expected. This review explores the potential use of antibody-based therapies to treat HD, including the rationale for this approach as well as the pre-clinical data supporting it. The potential challenges that will need to be considered if such route is to be pursued clinically are also discussed.
近年来，针对慢性神经退行性疾病的治疗和干预手段类型有了显著的扩展。除了各种不同的靶点，策略已经从症状管理转向更有针对性的疾病修饰方法。其中包括抗体疗法，这些疗法不仅正在针对一系列 tau 病和 synucleinopathies 进行评估，而且也正在成为中枢神经系统（CNS）单基因疾病的潜在应用，包括亨廷顿病（HD）。尽管针对此类疾病的反义寡核苷酸（ASO）治疗的早期试验数据令人兴奋，但抗体疗法可能是解决疾病另一个方面的关键，而这对于疾病的发病机制可能至关重要。虽然基于基因的方法旨在降低突变亨廷顿蛋白（mHtt）的水平，mHtt 是 HD 的遗传产物，主要在细胞成分内，但病理性蛋白在多种隔间中以游离形式和几种隔间中大量存在，包括脑脊液、血浆和细胞外基质。鉴于 mHtt 具有扩散和播种能力的证据不断增加，确实有必要在细胞内和细胞外靶向该蛋白。因此，mHtt 的游离形式不仅是抗体的理想靶点，而且如果要获得有意义和最大化的临床益处，就需要解决这个问题。本文综述了抗体疗法治疗 HD 的潜在用途，包括这种方法的原理以及支持它的临床前数据。如果要在临床上采用这种方法，还需要讨论潜在的挑战。
