A design-optimized engineered bacterium for enhanced efficacy and safety in treating tyrosinemia type 1: a multi-species preclinical study

Hereditary tyrosinemia type 1 (HT1) is a life-threatening metabolic disorder caused by the toxic accumulation of tyrosine and its metabolites. While treatment with nitisinone (NTBC) combined with a strict dietary regimen has improved outcomes, it imposes a significant lifelong burden and is associated with debilitating side effects and incomplete protection. Here, we developed an engineered probiotic with an optimized design, e-EcN-HT, and demonstrated its comprehensive efficacy and safety in HT1 across multiple animal models, including FAH -/- mice, FAH -/- rabbits, and Bama minipigs. Our findings indicate that e-EcN-HT not only mitigates multifaceted acute manifestations of FAH -/- mice, including neonatal death, acute liver injury, but also improves chronic liver lesions when combined with NTBC. The therapeutic effect translated successfully to the FAH -/- rabbit model. Moreover, e-EcN-HT administration led to the rapid metabolism of orally administered 13 C-tyrosine, confirming robust and active tyrosine consumption in pigs. Comprehensive safety assessments across murine and porcine models showed that e-EcN-HT was well-tolerated, with no significant adverse effects, systemic dissemination, or detrimental disruption to the resident gut microbiota. Collectively, our multi-species preclinical data underscore the potential of engineered bacteria as a viable therapeutic strategy for HT1 and possibly other metabolic disorders.