Biotherapeutic targeting gut-derived metabolites may ease autism symptoms, study finds

By Will Chu

- Last updated on GMT

Biotherapeutic targeting gut-derived metabolites may ease autism symptoms

Related tags Autism Axial metabolites

Targeting gut-derived metabolites with an oral biotherapeutic is effective in improving irritability and anxiety associated with autism spectrum disorder (ASD) according to Axial Therapeutics.

Newly published in Nature Medicine​, the study focuses on the US firm’s molecular therapeutic AB-2004 that is said to isolate certain gut-derived metabolites before they enter the bloodstream and reach the brain.

Axial think this gut-targeted approach minimises the potential for side effects partly due to a lack of systemic exposure to the drug.

“As we continue to advance AB-2004 through clinical development, we are excited to share these results which continue to support our previously published scientific research and preclinical data on the role of the gut-brain axis and its impact on neurological conditions,”​ says A. Stewart Campbell, study team member, Chief Executive Officer and Head of Research & Development at Axial.

“The data highlighted in Nature Medicine further support our novel therapeutic strategy focused on specific targets in the gut microbiome. We strongly believe that AB-2004 can improve the quality of life of many children with autism.”

Neuroactive microbial metabolites

The study, which includes researchers from California Institute of Technology and Queensland Children’s Hospital in Brisbane, Australia, specifically focus on gut-derived neuroactive microbial metabolites (NMMs)

According to the team these NMMs enter the bloodstream. adversely impacting behaviour by altering oligodendrocyte maturation and myelination in certain regions of the brain.

AB-2004 was shown to have strong safety and tolerability across all dose levels, and no drug-related serious adverse events were identified.

Further key findings revealed AB-2004 demonstrated target engagement as measured by significantly reduced levels of key gut bacterial metabolites, including 4-ethylphenyl sulphate (4EPS), in both urine and plasma.

AB-2004 also reduced anxiety and irritability based on scores on the Aberrant Behaviour Checklist - Irritability domain (ABC-I) and the Paediatric Anxiety Rating Scale (PARS).

Individuals with high baseline irritability (scores over 15), which represents the top quartile of severity, displayed a greater than nine-point decrease in ABC-I over eight weeks.

Addressing unmet treatment need

“The lack of safe and effective treatment options for co-occurring conditions associated with ASD, such as irritability and anxiety, exacerbate the daily challenges faced by children and their families,”​ explains Robert Hendren, Professor of psychiatry at the Weill Institute for Neurosciences at the University of California, and principal investigator for the AB-2004 Phase 2 trial.

“A gut-targeted therapeutic approach that safely mitigates the role of bacterial metabolites on traits associated with autism would be an ideal option for addressing the significant unmet treatment need.

“I am encouraged by the data from the first human study of AB-2004 and I look forward to assessing its potential as a safe alternative to atypical antipsychotics currently used to treat irritability associated with autism.”

Despite efforts over recent years, ASD remains poorly understood but is known to involve complex genetic risks with over 100 genes implicated to date, each with a small effect size.

A role for environmental risks in ASD has also been proposed, encompassing diet, maternal infection, exposure to toxins and changes in the gut microbiome.

Recent studies suggest that molecules produced in the GI tract can enter systemic circulation and affect immunity, metabolism and behaviour.

Altered immune and metabolic profiles have been associated with various neuropsychiatric disorders, such as ASD.

Additional studies identify the microbiome and metabolome as altered in individuals with ASD, anxiety, depression and schizophrenia.

4-ethylphenyl sulphate

“We previously identified several gut microbial metabolites that correlate with ASD-like symptoms in mice, and administration of one of these metabolites, 4-ethylphenyl sulphate (4EPS), to naive animals induced an anxiety-like phenotype,”​ the study points out.

“4EPS and several structurally related molecules are dysregulated in the faeces and plasma of individuals with ASD compared to control populations.

“Furthermore, an open-label faecal transplant study described improvements in GI and behavioural parameters in 18 individuals with ASD, with a partial restoration of metabolomic profiles.

“Although these early studies remain speculative, the prospect for ASD interventions targeting the microbiome or metabolome are both conceptually attractive and practically realisable.”

Source: Nat Med

Published online:

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

Authors: Stewart Campbell, A., Needham, B.D., Meyer, C.R. et al.

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