Intellectual disabilities (IDs) and autism spectrum disorders (ASDs) are co-occurring disorders that are first diagnosed at about 1-2 years of age. They affect approximately 2-3% of the population, between 1-2 million people in the UK alone have an ID/ASD. However, therapeutic approaches for these disorders tend to focus on managing symptoms using special education or medications that target specific symptoms such as anxiety and seizure. There is an urgent need to develop more effective treatments to reverse and/or prevent these brain disorders. Two areas of research have provided a sea change in how we envision potential treatments for ID/ASD. First, despite the fact that hundreds of genes have been implicated in causing ID/ASD, recent evidence suggests many genetic cause may share changes in brain development and hence treatment developed for one, may be effective for another. Second, while it was previously thought that there treatment would only be effective during early development when symptoms first appear, recent evidence suggests that at least some forms of these disorders may be treatable throughout the lifespan. Two of the most common genetic forms of ID/ASD are Fragile X Syndrome (FXS) and SYNGAP haploinsufficiency. Both result from genetic alteration of a single gene and hence, are relatively straightforward to study in the laboratory. Previous work from our laboratories indicates that these two disorders may share a common pathology in the hippocampus, the region of the brain responsible for many forms of learning and memory. Using novel rat models of these disorders, we propose to extend these studies to see whether they we also see similar changes in the regions of the brain that control emotion and anxiety, namely the amygdala and prefrontal cortex. We will also test whether any alterations can be prevented from emerging during development and can be rescued in older animals, once ID/ASD related symptoms have emerged. We will test three exciting new drug interventions that are currently being developed for treatment of FXS. Each intervention will be tested for their ability to rescue changes in brain cells, in the connections between brain cells, as well as the behavioural consequences that result from these alterations in brain development.

Efficient synthesis remains a bottleneck in the drug discovery process. Access to novel biologically active molecules to treat diseases continues to be a major bottleneck in the pharmaceutical industry, costing many lives and many £millions per year in healthcare investment and loss in productivity. In 2016, the Pharmaceutical Industry's estimated annual global spend on research and development (R&D) was over $157 billion. At a national level, the pharmaceutical sector accounted for almost half of the UK's 2016 £16.5bn R&D expenditure, with £700 million invested in pre-clinical small molecule synthesis, and 995 pharmaceutical related enterprises (big pharma, SMEs, biotech & CROs) employing around 23,000 personnel in UK R&D. The impact of this sector and its output on the nation's productivity is indisputable and worthy of investment in new approaches and technologies to fuel further innovation and development. With an increasing focus on precision medicine and genetic understanding of disease there will be to a dramatic increase in the number of potent and highly selective molecular targets; identifying genetically informed targets could double success rates in clinical development (Nat. Gen. 2015, 47, 856). However, despite tremendous advances in chemical research, we still cannot prepare all the molecules of potential interest for drug development due to cost constraints and tight commercial timelines. By way of example, Merck quote that 55% of the time, a benchmarked catalytic reaction fails to deliver the desired product; this statistic will be representative across pharma and will apply to many comparable processes. If more than half of the cornerstone reactions we attempt fail, then we face considerable challenges that will demand a radical and innovative a step change in synthesis. Such a paradigm shift in synthesis logic will need to be driven by a new generation of highly skilled academic and industry researchers who can combine innovative chemical synthesis and technological advances with fluency in the current revolution in data-driven science, machine learning methods and artificial intelligence. Synthetic chemists with such a set of skills do not exist anywhere in the world, yet the worldwide demand for individuals with the ability to work across these disciplines is increasing rapidly, and will be uniquely addressed by this proposed CDT. By training the next generation of researchers to tackle problems in synthetic chemistry using digital molecular technologies, we will create a unique, highly skilled research workforce that will address these challenges and place UK academic and industrial sectors at the frontier of molecule building science. The aspiration of next-generation chemical synthesis should be to prepare any molecule of interest without being limited by the synthetic methodologies and preparation technologies we have relied on to date. Synthetic chemists with the necessary set of such skills and exposure to the new technologies, required to innovate beyond the current limitations and deliver the paradigm shift needed to meet future biomedical challenges, are lacking in both academia and industry. To meet these challenges, the University of Cambridge proposes to establish a Centre of Doctoral Training in Automated Chemical Synthesis Enabled by Digital Molecular Technologies to recruit, train and develop the next generation of researchers to innovate and lead chemical synthesis of the future.