Synthetic live bacterial therapeutic for autism: preclinical proof-of-concept – SynBact4Autism

Autism spectrum disorders (ASD) are severe neurodevelopmental conditions with an increasing prevalence and currently no available cure. Innovative approaches for ASD treatment are thus critically needed. Gastrointestinal dysfunction, microbiota dysbiosis, and abnormally elevated levels of microbiota-produced metabolites (mMet) are observed in ASD patients. Recently, we demonstrated in rodents a causal relationship between elevated mMet and selective induction of ASD core symptoms (social deficits, repetitive behaviors), and GI symptoms (microbiota dysbiosis, GI dysfunction). Another mMet elevated in ASD patients is known to induce in rodents anxiety, a frequent ASD comorbidity. We propose that mMet upregulated in ASD are novel and relevant therapeutic targets to alleviate behavioral and GI symptoms in ASD patients.
Our project aims to deliver a preclinical proof-of-concept that therapeutic Live Bacterial Products (LBP) can reduce elevated gut mMet levels and correct ASD and GI symptoms in preclinical ASD models. We have identified bacterial multi-enzymatic pathways capable of metabolizing our target mMet into central metabolites. Combining computational biology and synthetic biology, we will first optimize pathways activity in the probiotic strain Escherichia coli Nissle 1917 (EcN), largely used in LBP therapeutic approaches. We will then engineer mMet-degrading EcN complying with EU regulatory requirements for clinical use and validate their efficiency in vitro and ex vivo. Finally, therapeutic EcN strains will be tested in ASD preclinical models to assess their safety, their effectiveness in reducing target mMet levels, and their efficiency in rescuing ASD behavioral and GI symptoms.
Our work will open critically needed new therapeutic avenues for ASD and pioneer the use of mMet-degrading LBP to treat neuropsychiatric disorders presenting with mMet dysregulation.