Targeting early-life intervention for treatment of neurodevelopmental disorders

针对早期生命干预治疗神经发育障碍

• 批准号: MR/Y014529/1
• 负责人: Sam Booker
• 金额: $ 69.75万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY014529%2F1
• 关键词: Targeting; early; life; intervention; treatment

During our lives we experience the world as a procession of sensations and events in locations that we encounter. Two critical functions for typical development are our sense of touch and our ability to remember places we have been. These abilities have a basis in brain circuits, which when functioning correctly allow us to generate an internal picture of the world around us. Changes to the function of these brain circuits can disrupt these abilities and lead to other features such as epileptic seizures, anxiety, autism, and sensory disturbances. Many such features are observed in individuals with neurodevelopmental conditions (such as Fragile X Syndrome), which together significantly impair day-to-day life, requiring substantial care and medical support. Fragile X Syndrome affects up to 1 in 5000 people, and is the most-common, inherited, single gene cause of intellectual disability and autism, with individuals often experiencing anxiety, epilepsy and sensory disturbances. Many of these features have been directly linked to the increased activity of individual brain cells (neurons) and the circuits they form during early-life development. Specifically, these features often appear during the life periods when neurons are most susceptible to changes in activity, which can lead to long-lasting changes in circuit function. This may explain why increased sensory experiences can benefits individuals with Fragile X Syndrome, as this directly supports the maturation of these brain circuits. However, most drug treatments for Fragile X Syndrome try to address negative features as they appear (such as epilepsy and anxiety). Such therapeutic approaches mean that multiple different drugs need to be taken by individuals to manage the many features experienced, which can lead to a wide range of side-effects. Therefore, there is a critical unmet need for new Fragile X Syndrome therapies that target as many features as possible. One such approach is to try and correct increased neural activity during early-life, before many clinical features emerge. However, most trials for new Fragile X Syndrome treatments are conducted later in development, or indeed in adulthood, missing this key developmental stage. One such drug, known as BPN-14,770, targets excessive neuronal activity, and has been shown to benefit adults with Fragile X Syndrome. However, based on research conducted by us and others, this drug may in fact produce the most profound and long-lasting benefits for individuals if given while brain circuits still maturing. To address this, our research aims to determine when during early-life development BPN-14,770 can correct changes not only single neuron function, but also the circuits they form that contribute to behaviour in later life. For the most part, this level of analysis is not possible in Fragile X individuals, as accessing living neurons from the brain is neither ethical nor possible. Therefore, for this research we will use a rat model of Fragile X Syndrome to understand how BPN-14,770 can correct the function of neurons in brain circuits that control sensory processing and memory formation. We will achieve this by recording the electrical activity of neurons, determining how they connect to each other and the strength of these connections; which we have previously shown to be altered in this Fragile X Syndrome rat model. We will then administer BPN-14,770, either alone or in combination with enhanced sensory experience during early life. The ages we will test broadly match those when features of Fragile X Syndrome are identified in children. We will assess if these giving this treatment earlier in life has the potential to correct multiple behavioural features of this Fragile X Syndrome rat model over the life-span. These research aims to direct not only future clinical trials using BPN-14,770, but also redefine our approach to the treatment of other neurodevelopmental conditions for generally.

在我们的一生中，我们将世界体验到我们遇到的地点的感觉和事件的游行。典型发展的两个关键功能是我们的触摸感和我们记住我们曾经去过的地方的能力。这些能力在脑电路中具有基础，在正常运行时，我们可以在周围的世界内部产生内部图片。这些大脑回路功能的变化会破坏这些能力，并导致其他特征，例如癫痫发作，焦虑，自闭症和感觉障碍。在具有神经发育状况的个体（例如脆弱的X综合征）中观察到许多此类特征，它们会严重损害日常生活，需要大量的护理和医疗支持。脆弱的X综合征最多影响5000人中的1人，并且是智障和自闭症的最常见的，单一的基因原因，个人经常患有焦虑，癫痫和感觉障碍。这些特征中的许多特征已直接与单个脑细胞（神经元）的活性增加以及它们在早期发育过程中形成的电路有关。具体而言，这些特征通常出现在神经元最容易受到活动变化的生命周期中，这可能导致电路功能的持久变化。这可能解释了为什么增加的感觉体验会使易碎X综合征的个体受益，因为这直接支持了这些大脑回路的成熟。但是，大多数脆弱X综合征的药物治疗都试图解决其出现的负面特征（例如癫痫和焦虑）。这种治疗方法意味着个人需要采用多种不同的药物来管理经历的许多特征，这可能导致广泛的副作用。因此，对新的X综合征疗法有一个至关重要的未满足需求，该疗法的目标是尽可能多的特征。一种这样的方法是在出现许多临床特征之前尝试纠正早期生活中增加的神经活动。但是，大多数针对新的脆弱X综合征治疗的试验是在发育后的后期或成年后进行的，缺少这个关键的发展阶段。一种这样的药物，称为BPN-14,770，靶向过多的神经元活性，并已被证明使患有易碎X综合征的成年人受益。但是，根据我们和其他人进行的研究，如果在脑电路仍在成熟的情况下给予个人，这种药物实际上可能对个人产生最深刻，最持久的好处。为了解决这个问题，我们的研究旨在确定何时在早期开发期间BPN-14,770何时可以纠正更改，不仅可以更改单个神经元功能，而且还可以纠正它们形成的电路，这些电路会导致后来的行为。在大多数情况下，在脆弱的X个个体中不可能进行这种分析水平，因为从大脑中访问活着的神经元既不是道德的也不可能。因此，对于这项研究，我们将使用脆弱X综合征的大鼠模型来了解BPN-14,770如何纠正控制感觉处理和记忆形成的脑电路中神经元的功能。我们将通过记录神经元的电活动，确定它们如何相互连接以及这些连接的强度来实现这一目标；我们以前已显示在这种脆弱的X综合征大鼠模型中改变了这一点。然后，我们将单独或与早期的感官体验相结合，管理BPN-14,770。当儿童鉴定出脆弱的X综合征的特征时，我们将测试的年龄与之相匹配。我们将评估这些在生命中的较早治疗是否有可能在生命中纠正这种脆弱的X综合征大鼠模型的多种行为特征。这些研究旨在不仅使用BPN-14,770指导将来的临床试验，而且还重新定义了我们通常对其他神经发育状况的方法。