Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial

Abstract

urrent estimates of ASD prevalence reach one in 54 children born in the United States 1 , and recent clinical failures [2][3][4][5][6][7][8][9] highlight the need to expand drug development efforts. Behavioral features and severity are measured by validated observational assessment tools, as there are no imaging-based or molecular biomarkers that reliably and objectively diagnose ASD. Furthermore, autism manifests across a broad spectrum, from minimally affected individuals to those who require intense support, and there are no approved drugs for core symptoms. The etiology of ASD is poorly understood and likely multifactorial but is known to involve complex genetic risks 10 , with over 100 genes implicated to date, each with a small effect size 11 . A role for environmental risks in ASD has also been proposed, encompassing diet 12 , maternal infection 13 , exposure to toxins 14 and changes in the gut microbiome 15 . The notion that fixed genetic predispositions coupled with variable environmental risks together manifest symptom severity is intriguing from a therapeutic perspective, because correcting mutations in the genome remains challenging, and reducing potential environmental contributors is likely more tractable. Recent studies suggest that molecules produced in the GI tract can enter systemic circulation and affect immunity 16 , metabolism 17 and behavior 18 . Altered immune and metabolic profiles have been associated with various neuropsychiatric disorders, such as ASD [19][20][21] , and the microbiome and metabolome are altered in individuals with ASD 19,22 , anxiety 23 , depression 24 and schizophrenia 25 . Notably, over a dozen studies have shown changes in the fecal microbiome in several ASD cohorts compared to controls 26 , although these associations do not resolve cause or effect. Dietary habits likely contribute to the ASD microbiome 27 . Several studies have also revealed changes in the metabolome of individuals with ASD from diverse geographies 19,[28][29][30] , with reports showing dysregulation of the fecal metabolome 19,[31][32][33] . We previously identified several gut microbial metabolites that correlate with ASD-like symptoms in mice, and administration of one of these metabolites, 4-ethylphenyl sulfate (4EPS), to naive animals Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial

Comprehensive characterization of multi-omic landscapes between gut-microbiota metabolites and the G-protein-coupled receptors in Alzheimer’s disease

“…While recent advances indicate that alterations of bacteria or microbiota-derived metabolites modulate neurological disorders 76 , insufficient understanding of the potential targets of microbial products largely limits novel therapy development and clinical translation. Notably, microbiota-based therapeutics have been employed to treat autism spectrum disorder 77 , which serve as a proof of principle that other novel therapies for brain health, including AD, may also be derived by targeting microbiota dysbiosis. In our study, we developed a conceptual ML-based structural systems pharmacogenomics framework based on cheminformatics and bioinformatics data.…”

Physical Activity, Gut Microbiota, and Genetic Background for Children and Adolescents with Autism Spectrum Disorder

“…AB-2004 is a spherical carbon adsorbent with a high surface area that is highly effective in removing uremic toxins, including those produced by gut bacteria. After 8 weeks of treatment with AB-2004, children with ASD showed improvements in anxiety, irritability, and gastrointestinal health [ 165 ].…”

Issues for patchy tissues: defining roles for gut-associated lymphoid tissue in neurodevelopment and disease

“…The microbiota-gut-brain axis modulates the body’s response to changes in the microbiota within the gastrointestinal (GI) tract, influencing gut function, bodily immune response, physiological stress and cognitive behaviour. Several studies indicate these complex interacting pathways are disturbed in neurodevelopmental disorders including autism spectrum disorder (ASD; autism) (Campbell et al 2022 ; Matta et al 2019 ; Mayer et al 2014 ; Sharon et al 2019 ; Morais et al 2021 ; Hughes et al 2018 ). Central to our understanding of the cellular basis for the microbiota-gut-brain axis is the gut-associated lymphoid tissue (GALT), a major component of the immune system, comprising multiple lymphoid masses located in the small intestine (i.e., Peyer’s patches), the appendix/caecum (i.e., caecal patch tissue) as well as in the large intestine and rectum.…”

“…As such, alterations in host, including changes in nervous system function and patterns of innervation, can influence the development and function of Peyer’s patches and caecal patch tissue. Furthermore, Liu and colleagues reported that host genetics could modify the microbiome (Liu et al 2016 ; Goodrich et al 2014 ), while recent compelling data indicate that modifications to gut microbial metabolites can lead to changes in brain structure and behaviour in the context of autism (Needham et al 2022 ; Campbell et al 2022 ). These recent studies altogether suggest that the microbiota-gut-brain axis, which includes the sensing of microbes and pathogens via GALT signalling, likely play important roles in neurodevelopmental disorders.…”