Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria

• DOI: 10.1038/s42003-021-02183-1
• Publication Date: 2021-07-22T16:03:18Z
• Authors: Mark R. Charbonneau; William S. Denney; Nicholas G. Horvath; Pasquale Cantarella; Mary J. Castillo; Marja K. Puurunen; Aoife M. Brennan
• Keywords: Phenylketonurias

Abstract The development of therapeutics depends on predictions clinical activity from pre-clinical data. We have previously described SYNB1618, an engineered bacterial therapeutic (synthetic biotic) for the treatment Phenylketonuria (PKU), a rare genetic disease that leads to accumulation plasma phenylalanine (Phe) and severe neurological complications. SYNB1618 consumes Phe in preclinical models, healthy human volunteers, PKU patients. However, it remains unclear what extent consumption by gastrointestinal tract lowers levels Here, we construct mechanistic model predicts function non-human primates subjects combining vitro simulations prior knowledge physiology. In addition, extend kinetics patients, order estimate lowering SYNB1618. This approach provides framework can be used more broadly define potential synthetic biotics.