LIMK1 inhibitors - A novel, disease-modifying approach for the treatment of fragile X syndrome

脆性X综合征(FXS)是导致学习障碍的最常见的遗传原因，每5000人中就有1人受到影响(男性比女性更常见)，患有FXS的男孩通常比女孩有更明显的临床症状。它的特点是学习困难、自闭症、行为挑战和社会、情感、注意力和语言问题，以及发展为癫痫的可能性。FXS的临床症状出现在儿童早期，一直持续到成年，到成年时，大多数FXS患者也已经发展成焦虑症。FXS是由单一基因(FMR1基因)的变化引起的，该基因改变了一种名为FMRP的蛋白质的产生。这种蛋白质在控制大脑中神经细胞之间的适当连接方面非常重要，使它们能够有效地进行交流。FMR1基因的这种变化阻止了FMRP蛋白的产生，并导致大脑发生变化，从而导致FXS的体征、行为和症状。最近几个实验室的发现揭示了FMRP蛋白丢失与大脑变化之间关系的关键发现。特别令人感兴趣的是另一种蛋白质LIMK1的发现，LIMK1是一种主调节蛋白，在FXS患者中过度活跃。我们的方法是设计能够抑制这种主调节蛋白的药物分子，并通过这样做，逆转FMRP蛋白丢失的影响。目前还没有批准用于FXS的药物。因此，我们相信这种方法有一个现实的机会，为脆性X患者提供一种独特的和变革性的治疗剂。

Fragile X syndrome (FXS) is the most common inherited cause of learning disabilities and it affects around 1 in 5000 individuals (more common in males than females), and boys with FXS generally have more pronounced clinical symptoms than girls. It is characterised by learning difficulties, autism, behavioural challenges and social, emotional, attention and language problems as well as the potential to develop epilepsy. The clinical symptoms appear in early childhood and last into adulthood by which time the majority of FXS patients have also developed an anxiety disorder.FXS is caused by a change in a single gene (the FMR1 gene) which alters production of a protein called FMRP. This protein is important in controlling the proper connection between nerve cells in the brain, allowing them to communicate effectively. This change in the FMR1 gene prevents production of the FMRP protein and leads to changes in the brain that result in the signs, behaviours and symptoms of FXS. Recent discoveries from several labs have uncovered key findings of the link between the loss of the FMRP protein and the changes that occur in the brain. Of particular interest has been the discovery of another protein, LIMK1, which acts as a master regulator and which is over-active in FXS individuals. Our approach is to design drug molecules which can inhibit this master regulator protein, and by doing so, reverse the impact of the loss of the FMRP protein. There are no currently approved drugs for FXS. Therefore, we believe this approach has a realistic chance to deliver a unique and transformative therapeutic agent for individuals with Fragile X.