Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders

Help for neurodevelopmental disorders When the brain does not develop normally, the disabilities that ensue can affect a person for life. Sahin and Sur review how emerging knowledge of the molecular biology behind a suite of neurodevelopmental disorders is shedding light on the group as a whole. The new knowledge offers tantalizing leads toward more effective therapies. Science, this issue p. 10.1126/science.aab3897 BACKGROUND Neurodevelopmental disorders are caused by abnormalities in the developing brain. Such abnormalities can occur as a result of germline or somatic mutations or because of epigenetic or environmental factors. These disorders affect a large number of children in the developed world, as well as the developing world. The societal cost of neurodevelopmental disorders is immense, making the pursuit of treatments for individuals with neurodevelopmental disorders a top unmet medical need. ADVANCES Research in the genetics of neurodevelopmental disorders such as autism suggests that several hundred genes are likely involved as risk factors for these disorders. This heterogeneity presents both a challenge and an opportunity for researchers. Although the exact identity of many of the genes remains to be discovered, functional analysis of genes underlying several single-gene disorders has yielded considerable progress. Most genes identified to date appear to encode proteins that serve certain conserved pathways: protein synthesis, transcriptional or epigenetic regulation, and synaptic signaling. Genetic syndromes such as fragile X syndrome, Rett syndrome, and tuberous sclerosis complex provide insights into the molecular pathways commonly affected in autism spectrum disorder (ASD). Understanding the basic biology of these diseases has led to mechanism-based treatment designs. These genetic disorders, once thought to be irreversible, are now the subject of trailblazing new clinical trials for neurodevelopmental disorders. On the basis of research in genetic mouse models, it is hypothesized that different genetic disorders will respond to different therapies, such as mammalian target of rapamycin inhibitors (tuberous sclerosis and PTEN hamartoma tumor syndrome), metabotropic glutamate receptor 5 antagonists (fragile X and 16p11.2 deletion), and insulin-like growth factor 1 (Rett and Phelan-McDermid syndromes). It is not yet clear whether such trials will result in approval of the drugs for these specific conditions. Subsets of nonsyndromic autism patients may also benefit from one of these therapies, but further investigation will be required to provide the tools and methods to stratify the individuals with nonsyndromic autism into treatment groups. A remaining hurdle is the lack of precise understanding about the brain regions and neuronal circuits underlying autism. Studies in mouse models of autism suggest abnormalities in specific brain regions, as well as in certain cell types. Excitatory and inhibitory neurons in the neocortex, as well as subcortical structures such as basal ganglia and cerebellum, have been implicated. Astrocytes and microglia also play roles in ASD. Further studies will be required to provide definitive evidence that similar brain regions, cell types, and circuits are relevant to autism symptoms in the human brain. OUTLOOK The next generation of research in neurodevelopmental disorders must address the neural circuitry underlying behavioral symptoms and comorbidities, the cell types in these circuits, and common signaling pathways that link diverse genes. Early attempts at treating neurodevelopmental disorders have yielded mixed results, underscoring the necessity of choosing the right cohort of patients to treat, developing more sensitive and dynamic outcome measures, using cogent biomarkers, and utilizing technologies such as stem cell–derived neurons to predict response to treatment. Biomarkers can be helpful in predicting subjects most likely to respond, confirm target engagement, and detect early signals of efficacy. Given that ASD represents circuit dysfunction, biomarkers that allow us to analyze autism-related circuit function are likely to be most relevant. Especially, translatable biomarkers that can be used in both mouse models and human subjects, such as electroencephalography, magnetic resonance imaging, visual or auditory evoked potentials, and eye-blink conditioning, can be particularly powerful. One potential new tool to identity those who are likely to respond is induced pluripotent stem cell (iPSC)–derived neurons. This technology allows the possibility of testing the effects of a compound on a patient’s neurons before it is given to the patient. Modeling the effects of mutations in iPSC-derived neurons can be informative about the molecular and cellular defects underlying autism. Only when we can leverage the heterogeneity of neurodevelopmental disorders into precision medicine will the mechanism-based therapeutics for these disorders start to unlock success. Translational research and clinical trials in ASD. Translational studies in ASD have gained momentum from genetically defined causes such as fragile X syndrome (FXS), Rett syndrome (RTT), and tuberous sclerosis complex (TSC). The patients with these disorders are phenotyped in detail by means of advanced imaging and electrophysiology studies, with the aim of identifying potential biomarkers. There are cell-based models (both rodent and human) as well as mouse models of these syndromes, enabling preclinical trials. Together, these efforts have led to clinical trials in some of these disorders. It is important to remember that the discovery cycle will likely take more than one round to achieve safe and effective therapies for these disorders. Research in the genetics of neurodevelopmental disorders such as autism suggests that several hundred genes are likely risk factors for these disorders. This heterogeneity presents a challenge and an opportunity at the same time. Although the exact identity of many of the genes remains to be discovered, genes identified to date encode proteins that play roles in certain conserved pathways: protein synthesis, transcriptional and epigenetic regulation, and synaptic signaling. The next generation of research in neurodevelopmental disorders must address the neural circuitry underlying the behavioral symptoms and comorbidities, the cell types playing critical roles in these circuits, and common intercellular signaling pathways that link diverse genes. Results from clinical trials have been mixed so far. Only when we can leverage the heterogeneity of neurodevelopmental disorders into precision medicine will the mechanism-based therapeutics for these disorders start to unlock success.