Çaku Artuela, Pellerin David, Bouvier Paméla, Riou Emilie, Corbin Francois
Department of Biochemistry, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Am J Med Genet A. 2014 Nov;164A(11):2834-42. doi: 10.1002/ajmg.a.36750. Epub 2014 Sep 24.
Fragile X syndrome (FXS) results from dynamic mutations leading ultimately to the absence of expression of the Fragile X Mental Retardation Protein (FMRP). It is characterized by synaptic upregulated protein synthesis and immature dendritic spines associated with altered brain plasticity and cognitive functions. Recent work in Fmr1 knockout mice has shown that lovastatin, an inhibitor of Ras-ERK1/2, normalized hippocampus protein synthesis. We hypothesize that lovastatin, as a disease-modifying drug, would counterweigh the absence of FMRP and improve behavior. Here we report a phase I study to assess the safety and efficacy of lovastatin in individuals with FXS. A total of 15 patients (13 males, 6-31 years old) were treated with escalating doses of lovastatin (up to 40 mg) for three months. Their behavior were assessed before and after treatment using the Aberrant Behavioral Checklist--Community (ABC-C) total score (primary outcome), as well as domains of the FXS validated version of the ABC-C (secondary outcomes). The treatment was well tolerated and minimal side effects were reported. Significant improvement in the primary outcome (P<0.005), as well as in secondary outcomes, were observed in the majority of the subjects (12/15). We think that long-term sustained treatment with diseased-modifying drugs would be necessary in order to improve behavior and ultimately learning. Lovastatin, well known for its long-term security profile, would be a good candidate for that purposes. Our study showing reassuring safety data along with potential functional benefit emphasizes the need of a placebo-controlled trial to ascertain lovastatin efficacy in FXS individuals.
脆性X综合征（FXS）由动态突变引起，最终导致脆性X智力低下蛋白（FMRP）表达缺失。其特征为突触蛋白合成上调以及树突棘不成熟，这与大脑可塑性和认知功能改变相关。最近在Fmr1基因敲除小鼠中的研究表明，洛伐他汀（一种Ras - ERK1/2抑制剂）可使海马体蛋白合成恢复正常。我们推测，洛伐他汀作为一种疾病修饰药物，能够抵消FMRP缺失的影响并改善行为。在此，我们报告一项I期研究，以评估洛伐他汀对FXS患者的安全性和疗效。总共15名患者（13名男性，6 - 31岁）接受了递增剂量的洛伐他汀（最高40毫克）治疗，为期三个月。在治疗前后，使用异常行为检查表 - 社区版（ABC - C）总分（主要结局）以及ABC - C的FXS验证版各领域（次要结局）对他们的行为进行评估。治疗耐受性良好，报告的副作用极小。大多数受试者（12/15）在主要结局（P<0.005）以及次要结局方面均有显著改善。我们认为，为了改善行为并最终提高学习能力，有必要使用疾病修饰药物进行长期持续治疗。洛伐他汀因其长期安全性而闻名，将是实现此目的的良好候选药物。我们的研究显示了令人安心的安全性数据以及潜在的功能益处，强调需要进行安慰剂对照试验以确定洛伐他汀对FXS患者的疗效。
