Merola Aristide, Kobayashi Noelle, Romagnolo Alberto, Wright Brenton A, Artusi Carlo Alberto, Imbalzano Gabriele, Litvan Irene, Van Laar Amber D, Bankiewicz Krystof
Department of Neurology, Madden Center for Parkinson Disease and Other Movement Disorders, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
The Ohio State University, Columbus, OH, United States.
Front Neurol. 2021 Apr 6;12:648532. doi: 10.3389/fneur.2021.648532. eCollection 2021.
We sought to provide an overview of the published and currently ongoing movement disorders clinical trials employing gene therapy, defined as a technology aiming to modulate the expression of one or more genes to achieve a therapeutic benefit. We systematically reviewed movement disorders gene therapy clinical trials from PubMed and ClinicalTrials.gov using a searching strategy that included Parkinson disease (PD), Huntington disease (HD), amino acid decarboxylase (AADC) deficiency, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dystonia, tremor, ataxia, and other movement disorders. Data extracted included study characteristics, investigational product, route of administration, safety/tolerability, motor endpoints, and secondary outcomes (i.e., neuroimaging, biomarkers). We identified a total of 46 studies focusing on PD (21 published and nine ongoing), HD (2 published and 5 ongoing), AADC deficiency (4 published and 2 ongoing), MSA (2 ongoing), and PSP (1 ongoing). In PD, intraparenchymal infusion of viral vector-mediated gene therapies demonstrated to be safe and showed promising preliminary data in trials aiming at restoring the synthesis of dopamine, enhancing the production of neurotrophic factors, or modifying the functional interaction between different nodes of the basal ganglia. In HD, monthly intrathecal delivery of an antisense oligonucleotide (ASO) targeting the huntingtin protein (HTT) mRNA proved to be safe and tolerable, and demonstrated a dose-dependent reduction of the cerebrospinal fluid levels of mutated HTT, while a small phase-I study testing implantable capsules of cells engineered to synthesize ciliary neurotrophic factor failed to show consistent drug delivery. In AADC deficiency, gene replacement studies demonstrated to be relatively safe in restoring catecholamine and serotonin synthesis, with promising outcomes. Ongoing movement disorders clinical trials are focusing on a variety of gene therapy approaches including alternative viral vector serotypes, novel recombinant genes, novel delivery techniques, and ASOs for the treatment of HD, MSA, and distinct subtypes of PD (LRRK2 mutation or GBA1 mutation carriers). Initial phase-I and -II studies tested the safety and feasibility of gene therapy in PD, HD, and AADC deficiency. The ongoing generation of clinical trials aims to test the efficacy of these approaches and explore additional applications for gene therapy in movement disorders.
我们试图对已发表的以及目前正在进行的采用基因治疗的运动障碍临床试验进行概述，基因治疗被定义为一种旨在调节一个或多个基因的表达以获得治疗益处的技术。我们使用一种搜索策略，从PubMed和ClinicalTrials.gov系统回顾了运动障碍基因治疗临床试验，该策略涵盖帕金森病（PD）、亨廷顿病（HD）、氨基酸脱羧酶（AADC）缺乏症、多系统萎缩（MSA）、进行性核上性麻痹（PSP）、肌张力障碍、震颤、共济失调及其他运动障碍。提取的数据包括研究特征、研究产品、给药途径、安全性/耐受性、运动终点以及次要结果（即神经影像学、生物标志物）。我们共识别出46项研究，其中针对PD的有21项已发表研究和9项正在进行的研究，针对HD的有2项已发表研究和5项正在进行的研究，针对AADC缺乏症的有4项已发表研究和2项正在进行的研究，针对MSA的有2项正在进行的研究，针对PSP的有1项正在进行的研究。在PD中，脑实质内注射病毒载体介导的基因治疗已证明是安全的，并且在旨在恢复多巴胺合成、增强神经营养因子产生或改变基底神经节不同节点之间功能相互作用的试验中显示出有前景的初步数据。在HD中，每月鞘内递送靶向亨廷顿蛋白（HTT）mRNA的反义寡核苷酸（ASO）已证明是安全且可耐受的，并显示出突变型HTT的脑脊液水平呈剂量依赖性降低，而一项测试可植入的经工程改造以合成睫状神经营养因子的细胞胶囊的小型I期研究未能显示出一致的药物递送效果。在AADC缺乏症中，基因替代研究在恢复儿茶酚胺和5-羟色胺合成方面已证明相对安全，并取得了有前景的结果。目前正在进行的运动障碍临床试验聚焦于多种基因治疗方法，包括替代病毒载体血清型、新型重组基因、新型递送技术以及用于治疗HD、MSA和不同亚型PD（LRRK2突变或GBA1突变携带者）的ASO。最初的I期和II期研究测试了基因治疗在PD、HD和AADC缺乏症中的安全性和可行性。目前正在进行的一系列临床试验旨在测试这些方法的疗效，并探索基因治疗在运动障碍中的其他应用。
