Targeting early-life intervention for treatment of neurodevelopmental disorders

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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.