An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans.

Autor: Kurtz CB; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA. caroline@synlogictx.com., Millet YA; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA., Puurunen MK; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA., Perreault M; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA., Charbonneau MR; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA., Isabella VM; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA., Kotula JW; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA., Antipov E; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA., Dagon Y; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA., Denney WS; Diversigen Inc., 1 Baylor Plaza, Houston, TX 77030, USA., Wagner DA; Metabolic Solutions Inc., 460 Amherst Street, Nashua, NH 03063, USA., West KA; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA., Degar AJ; Diversigen Inc., 1 Baylor Plaza, Houston, TX 77030, USA., Brennan AM; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA., Miller PF; Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2019 Jan 16; Vol. 11 (475).
DOI: 10.1126/scitranslmed.aau7975
Abstrakt: The intestine is a major source of systemic ammonia (NH 3 ); thus, capturing part of gut NH 3 may mitigate disease symptoms in conditions of hyperammonemia such as urea cycle disorders and hepatic encephalopathy. As an approach to the lowering of blood ammonia arising from the intestine, we engineered the orally delivered probiotic Escherichia coli Nissle 1917 to create strain SYNB1020 that converts NH 3 to l-arginine (l-arg). We up-regulated arginine biosynthesis in SYNB1020 by deleting a negative regulator of l-arg biosynthesis and inserting a feedback-resistant l-arg biosynthetic enzyme. SYNB1020 produced l-arg and consumed NH 3 in an in vitro system. SYNB1020 reduced systemic hyperammonemia, improved survival in ornithine transcarbamylase-deficient spf ash mice, and decreased hyperammonemia in the thioacetamide-induced liver injury mouse model. A phase 1 clinical study was conducted including 52 male and female healthy adult volunteers. SYNB1020 was well tolerated at daily doses of up to 1.5 × 10 12 colony-forming units administered for up to 14 days. A statistically significant dose-dependent increase in urinary nitrate, plasma 15 N-nitrate (highest dose versus placebo, P = 0.0015), and urinary 15 N-nitrate was demonstrated, indicating in vivo SYNB1020 activity. SYNB1020 concentrations reached steady state by the second day of dosing, and excreted cells were alive and metabolically active as evidenced by fecal arginine production in response to added ammonium chloride. SYNB1020 was no longer detectable in feces 2 weeks after the last dose. These results support further clinical development of SYNB1020 for hyperammonemia disorders including urea cycle disorders and hepatic encephalopathy.
(Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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