Emerging Epigenetic Therapeutics and Diagnostics for Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a complex neurological and developmental condition that occurs in approximately 1 in 100 children. ASD is a lifelong condition defined by difficulties with social communication, restricted interests, and repetitive behaviors, among other symptoms. Currently, we understand that there is no cure and the disorder can only be managed with occupational therapy alongside limited medical treatments. Reasons underlying the pathogenesis of ASD are still not well understood, but recent studies point to the influence of epigenetic dysregulation in ASD development, which opens up avenues to novel diagnosis and treatment options. In this review, we summarize recent findings and emerging therapeutics for ASD, with a focus on implications of epigenetic regulatory pathways and factors. We expound the implications of these findings to enable preventive measurements for mothers to reduce the impact of ASD at birth, non-invasive diagnostic tests for early detection, and personalized medicine management. Finally, we discuss several critical issues to be addressed and future directions of this important research field.

Keywords: ASD; autism; autism spectrum disorder; epigenetic; maternal immune activation; methylation; microbiome; perinatal.

Figure 1

Dual role of histamine. Histamine takes part in both inflammatory and regulatory pathways. Multiple studies have proven that histamine plays a protective role under lipopolysaccharide (LPS) challenges or inflammatory conditions. The use of H3R antagonists to block the reuptake of histamine by H3R has been shown to enhance histamine release and inhibit chronic microglia activation. Under such inflammatory conditions, histamine protects dopaminergic neurons from degeneration, enhancing alertness and memory in VPA-exposed mouse models. Thus, histamine antagonists such as ciproxifan are promising therapeutics for ameliorating ASD phenotypes in MIA-exposed offspring.

Figure 2

Maternal immune activation (MIA) and nutritional intake for the developing baby. Maternal immune activation (MIA) can be induced by a number of factors, including obesity, diabetes, infection, and oxidative stress. MIA activates microglia which release pro-inflammatory cytokines that recruit immune cells and amplify the inflammatory response. The placenta provides oxygen and nutrients to the developing baby through the umbilical cord while also removing waste and filtering out potentially harmful teratogenic chemicals. The mother’s cytokines can induce an inflammatory response in the developing baby and, if they penetrate the blood–brain barrier, induce neuroinflammation. Microglia can also be primed in a process called innate immune memory, which can lead to long-term deficits in microglia function. Maternal nutritional intake also has a direct impact on offspring health, as a high-fat diet is a risk factor for ASD pathogenesis. Contrarily, prenatal nutritional interventions can reduce the risk of offspring developing ASD or ameliorate ASD-associated symptoms.

Figure 3

Potential epigenetic targets for the treatment of ASD. (A) Role of estrogen, KDM6B, Zmiz1, and MSNP1AS in the regulation of mTOR activity. Everolimus and rapamycin directly inhibit mTOR. K27: histone H3 lysine 27; me: methylation. (B) Effect of different epigenetic factors and lithium in modulating WNT signaling activity. K4: histone H3 lysine 4; β-cat: beta-catenin. (C) ASH1L activates the expression of NTRK2, which is important in BDNF-TrkB signaling. (D) The hyperactivation of Notch signaling inhibits DNA methyltransferases DNMT3A and DNMT3B expression, in turn reducing the expression of autophagy-related genes, leading to ASD. Zigzag arrows: the dysregulation of these signaling pathways lead to ASD. Up arrow: upregulation. Down arrow: downregulation.

Figure 4

Gut–brain axis and altered gut microbiome compositions in ASD patients. The gut–brain axis is a bidirectional connection between the brain and the GI tract facilitated by the vagus nerve. ASD patients have altered gut microbiome compositions characterized by a decrease in diversity, an increase in harmful bacteria such as Clostridium which produce toxic metabolites such as PPA, and a decrease in beneficial bacteria (Bifidobacterium) and butyrate-producing bacteria (Faecalibacterium and Coprococcus), which maintain intestinal barrier integrity. Leaky gut or gut dysbiosis is a state of increased intestinal permeability that leads to GI inflammation. Furthermore, leaky gut allows the greater passage of toxic metabolites which can potentially cross the blood–brain barrier and cause neuroinflammation. Dietary interventions and probiotics can correct gut microbial compositions, reducing GI inflammation and ameliorating ASD behavioral symptoms. Up arrow: increase. Down arrow: decrease.