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

Abstract

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.

Figure 1. Molecular pathways implicated in neurodevelopmental disorders

Many of the genes mutated in individuals with ASD fall into several shared neuronal processes: transcriptional control and chromatin remodeling in the nucleus, protein synthesis, and synaptic structure. Proteins encoded by genes mutated in syndromes with high penetrance of ASD are shown with green outline. Many of the proteins (such as MECP2 and FMRP) have multiple functions and interactions in the cell, but are represented with the dominant functional role for the sake of clarity. Abbreviations not found in text include: RTKs = receptor tyrosine kinases; mGluRs = metabotropic glutamate receptors; iGluRs = metabotropic glutamate receptors; PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha); SREBP = sterol-response binding proteins; HIF1α = hypoxia inducible factor 1 alpha; ULK1 = unc-51-like kinase 1; ARC = Activity-Regulated Cytoskeleton-Associated Protein; UBE3A = Ubiquitin Protein Ligase E3A.

Figure 2. Hypothetical matrix of genetic mutations and brain regions mapping onto behavioral profiles

The approach to focus on mechanistic descriptions of symptom clusters rather than symptom inventories requires an understanding of the neural circuit(s) underlying these behavioral symptoms. One way to examine the neural circuits in animal models is to probe the relationship between a gene’s function in a certain brain region and the behavioral deficits in the animal. Use of conditional knockout mice has started to provide such information in certain genetic diseases such as TSC and RTT (93, 118). This matrix represents a hypothetical framework, which needs to be populated by future experimentation. One concrete example of this approach is currently in effect in epilepsy. Absence seizures are thought to arise from voltage-gated calcium channel dysfunction in the thalamus and respond best to ethosuximide treatment. In contrast, complex partial seizures occur due to increased excitation or decreased inhibition and thus respond to glutamate antagonists or GABAergic agonists. Such delineation of genetic, cellular and circuit defects may prove helpful in treating behavioral deficits associated with ASD with better precision as well.

Figure 3. Translational research and clinical trials in ASD

Translational studies in ASD have gained momentum from genetically defined causes such as FXS, TSC and RTT. The patients with these disorders are phenotyped in detail using 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. Based on the preclinical trials, the hypothesis is that different etiologies of ASD will respond to different therapies such as mTOR inhibitors (TSC and PTEN), mGluR5 antagonists (FXS and 16p11.2 deletion) and IGF-1 (RTT and PMS). Subsets of non-syndromic ASD patients may also benefit from one of these therapies, but further studies will be required to provide the tools and methods to stratify the individuals with non-syndromic ASD into treatment groups. It is important to remember that the discovery cycle will likely take more than one round in order to achieve safe and effective therapies for these disorders.