Munshi Kaizad, Pawlowski Katherine, Gonzalez-Heydrich Joseph, Picker Jonathan D
1 Department of Psychiatry, Boston Children's Hospital , Boston, Massachusetts.
2 Harvard Medical School , Boston, Massachusetts.
J Child Adolesc Psychopharmacol. 2017 Dec;27(10):850-863. doi: 10.1089/cap.2016.0200. Epub 2017 May 5.
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability, in addition to being the commonest diagnosable cause of autism. The identification of the biochemical mechanism underlying this disorder has provided amenable targets for therapy. This review aims to provide an overview of investigational drug therapies for FXS.
The authors carried out a search of clinical and preclinical trials for FXS in PubMed and on the U.S. National Institutes of Health index of clinical trials ( www.clinicaltrials.gov ). We limited our review to Phase II trials or more preliminary and reviewed the associated publications for these studies, complemented by a review of the literature on PubMed.
The review of the preclinical, Phase I, and Phase II trials of agents with therapeutic potential in FXS revolves around an understanding of the putative pathways in the pathogenesis of FXS. While there is significant overlap between some of these pathways, the agents can be categorized as modulators of the metabotropic glutamate receptor system, GABAergic agents, and miscellaneous modulators affecting other pathways.
As trials involving agents targeting different aspects of the molecular biology proceed, common themes have emerged. With the great hope came great disappointment as the initial trials failed to demonstrate sufficient significance. In particular, the differences in outcome between the animal models and humans have highlighted the unique challenges of carrying out trials in these cognitively and behaviorally challenged individuals, as well as a dearth of clinically relevant outcome measures for use in medication trials. However, in reviewing and reframing the studies of the last decade, many important lessons have been learned, which will ultimately have a greater impact on therapeutic research in the field of developmental delay as a whole.
脆性X综合征（FXS）是智力残疾最常见的遗传性病因，也是自闭症最常见的可诊断病因。对该疾病潜在生化机制的识别为治疗提供了合适的靶点。本综述旨在概述脆性X综合征的研究性药物治疗。
作者在PubMed和美国国立卫生研究院临床试验索引（www.clinicaltrials.gov）上搜索了脆性X综合征的临床和临床前试验。我们将综述限制在II期试验或更早期的试验，并查阅了这些研究的相关出版物，同时辅以PubMed上的文献综述。
对脆性X综合征具有治疗潜力的药物的临床前、I期和II期试验的综述围绕对脆性X综合征发病机制中假定途径的理解展开。虽然其中一些途径存在显著重叠，但这些药物可分为代谢型谷氨酸受体系统调节剂、GABA能药物以及影响其他途径的杂类调节剂。
随着针对分子生物学不同方面的药物试验的进行，出现了一些共同主题。伴随着巨大的希望而来的是巨大的失望，因为最初的试验未能显示出足够的显著性。特别是，动物模型和人类之间的结果差异凸显了在这些认知和行为有障碍的个体中进行试验的独特挑战，以及药物试验中缺乏临床相关的结局指标。然而，在回顾和重新审视过去十年的研究时，我们学到了许多重要经验教训，这些经验教训最终将对整个发育迟缓领域的治疗研究产生更大影响。
