An engineered bacterial therapeutic lowers urinary oxalate in preclinical models and in silico simulations of enteric hyperoxaluria

Abstract

Enteric hyperoxaluria (EH) is a metabolic disease caused by excessive absorption of dietary oxalate leading to the formation of chronic kidney stones and kidney failure. There are no approved pharmaceutical treatments for EH. SYNB8802 is an engineered bacterial therapeutic designed to consume oxalate in the gut and lower urinary oxalate as a potential treatment for EH. Oral administration of SYNB8802 leads to significantly decreased urinary oxalate excretion in healthy mice and non‐human primates, demonstrating the strain's ability to consume oxalate in vivo . A mathematical modeling framework was constructed that combines in vitro and in vivo preclinical data to predict the effects of SYNB8802 administration on urinary oxalate excretion in humans. Simulations of SYNB8802 administration predict a clinically meaningful lowering of urinary oxalate excretion in healthy volunteers and EH patients. Together, these findings suggest that SYNB8802 is a promising treatment for EH.

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“…C-SAA retained its original crystal structure after oxalic acid impregnation. And at 14.89 °and 47.36 °, two faint new diffraction peaks appeared, which may be oxalic acid hydroxyl groups generated on the surface of the modified material (Lubkowicz et al, 2022).…”

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“…By using the large repertoire of synthetic biology tools, bacteria can be reprogrammed to specifically target a disease, resulting in a highly precise autonomous therapy. Such therapies have been developed to target metabolic diseases, − prevent cancer, − inhibit pathogens, , and address other conditions − (for recent reviews, see refs − ). An increasing number of such studies have been reported thus far.…”

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“…This can be due to genetic defects, or via gastrointestinal conditions that increase oxalate uptake (Witting et al, 2021). Currently, there are no approved pharmaceutical treatments for this condition (Lubkowicz et al, 2022). SYNB8802 was modified to express genes from the oxalate degradation pathway of Oxalobacter formigenes, alongside an oxalyl-CoA synthetase gene.…”

“…SYNB8802 was modified to express genes from the oxalate degradation pathway of Oxalobacter formigenes, alongside an oxalyl-CoA synthetase gene. These modifications conferred the ability for SYNB8802 to degrade oxalate in vitro (Lubkowicz et al, 2022). As with SYN1618, SYNB8802 was tested in mouse and non-human primate models; demonstrating that SYNB8802 could reduce the excreted levels of urinary oxalate (Lubkowicz et al, 2022).…”

“…These modifications conferred the ability for SYNB8802 to degrade oxalate in vitro (Lubkowicz et al, 2022). As with SYN1618, SYNB8802 was tested in mouse and non-human primate models; demonstrating that SYNB8802 could reduce the excreted levels of urinary oxalate (Lubkowicz et al, 2022). A phase I clinical trial (NCT04629170) is now recruiting healthy adults and EH patients, to evaluate the safety and efficacy of SYNB8802 in humans.…”