Davenport Matthew H, Schaefer Tori L, Friedmann Katherine J, Fitzpatrick Sarah E, Erickson Craig A
Division of Child and Adolescent Psychiatry (MLC 4002), Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229-3039, USA.
Department of Biomedical Engineering, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, 45221, USA.
Drugs. 2016 Mar;76(4):431-45. doi: 10.1007/s40265-016-0542-y.
To date, no drug is approved for the treatment of Fragile X Syndrome (FXS) although many drugs are used to manage challenging behaviors from a symptomatic perspective in this population. While our understanding of FXS pathophysiology is expanding, efforts to devise targeted FXS-specific treatments have had limited success in placebo-controlled trials. Compounds aimed at rectifying excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission, as well as other signaling pathways known to be affected by Fragile X Mental Retardation Protein (FMRP) are under various phases of development in FXS. With the failure of several metabotropic glutamate receptor subtype 5 (mGlur5) selective antagonists under clinical investigation, no clear single treatment appears to be greatly effective. These recent challenges call into question various aspects of clinical study design in FXS. More objective outcome measures are under development and validation. Future trials will likely be aimed at correcting multiple pathways known to be disrupted by the loss of FMRP. This review offers a brief summary of the prevalence, phenotypic characteristics, genetic causes and molecular functions of FMRP in the brain (as these have been extensively reviewed elsewhere), discusses the most recent finding in FXS drug development, and summarizes FXS trials utilizing symptomatic treatment.
迄今为止，尚无药物被批准用于治疗脆性X综合征（FXS），尽管从对症治疗的角度来看，许多药物被用于管理该人群中具有挑战性的行为。虽然我们对FXS病理生理学的理解正在不断扩展，但在安慰剂对照试验中，设计针对性的FXS特异性治疗方法的努力取得的成功有限。旨在纠正谷氨酸过量和γ-氨基丁酸（GABA）神经传递不足的化合物，以及已知受脆性X智力低下蛋白（FMRP）影响的其他信号通路，在FXS的治疗中正处于不同的研发阶段。随着几种临床研究中的代谢型谷氨酸受体5（mGlur5）选择性拮抗剂试验失败，似乎没有一种明确的单一治疗方法具有显著疗效。这些近期的挑战引发了对FXS临床研究设计各个方面的质疑。更客观的疗效指标正在研发和验证中。未来的试验可能旨在纠正已知因FMRP缺失而被破坏的多种信号通路。本综述简要总结了FMRP在大脑中的患病率、表型特征、遗传原因和分子功能（因为这些内容在其他地方已有广泛综述），讨论了FXS药物研发的最新发现，并总结了使用对症治疗的FXS试验。
