PDF(Pubmed)
Abstract：
Fragile X syndrome is the most common inherited intellectual disability and mono-genetic cause of autism spectrum disorder. It is a neurodevelopmental condition occurring due to a CGG trinucleotide expansion in the FMR1 gene. Polymorphisms and variants in large-conductance calcium-activated potassium channels are increasingly linked to intellectual disability and loss of FMR protein causes reduced large-conductance calcium-activated potassium channel activity leading to abnormalities in synapse function. Using the cannabinoid-like large-conductance calcium-activated potassium channel activator VSN16R we rescued behavioural deficits such as repetitive behaviour, hippocampal dependent tests of daily living, hyperactivity and memory in a mouse model of fragile X syndrome. VSN16R has been shown to be safe in a phase 1 study in healthy volunteers and in a phase 2 study in patients with multiple sclerosis with high oral bioavailability and no serious adverse effects reported. VSN16R could therefore be directly utilized in a fragile X syndrome clinical study. Moreover, VSN16R showed no evidence of tolerance, which strongly suggests that chronic VSN16R may have great therapeutic value for fragile X syndrome and autism spectrum disorder. This study provides new insight into the pathophysiology of fragile X syndrome and identifies a new pathway for drug intervention for this debilitating disorder.
摘要：
脆性X综合征是最常见的遗传性智力障碍和自闭症谱系障碍的单遗传原因。这是由于FMR1基因中CGG三核苷酸扩增而发生的神经发育状况。大电导钙激活钾通道中的多态性和变异与智力障碍和FMR蛋白丢失越来越相关，导致大电导钙激活钾通道活性降低，导致突触功能异常。使用大麻素样的大电导钙激活钾通道激活剂VSN16R，我们挽救了行为缺陷，例如重复行为，海马依赖性日常生活测试，脆性X综合征小鼠模型的多动和记忆。在健康志愿者的1期研究和多发性硬化症患者的2期研究中，VSN16R已被证明是安全的，具有高口服生物利用度，没有严重的不良反应报告。因此,VSN16R可直接用于脆性X综合征临床研究。此外，VSN16R没有显示出耐受性的证据，这强烈表明慢性VSN16R可能对脆性X综合征和自闭症谱系障碍有很大的治疗价值。这项研究为脆性X综合征的病理生理学提供了新的见解，并确定了药物干预这种使人衰弱的疾病的新途径。
