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AssigneeSynlogic Operating Company, Inc.
InventorsVincent M. Isabella, Sean Cotton, Jian-Rong Gao, Teodelinda Mirabella, Christopher George Bergeron
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The present disclosure provides recombinant bacterial cells that have been engineered with genetic circuitry which allow the recombinant bacterial cells to sense a patient's internal environment and respond by turning an engineered metabolic pathway on or off. When turned on, the recombinant bacterial cells complete all of the steps in a metabolic pathway to achieve a therapeutic effect in a host subject. These recombinant bacterial cells are designed to drive therapeutic effects throughout the body of a host from a point of origin of the microbiome. Specifically, the present disclosure provides recombinant bacterial cells that comprise a uric acid catabolism enzyme, e.g., a uric acid degrading enzyme, for the treatment of diseases and disorders associated with uric acid, including hyperuricemia and gout, in a subject. The disclosure further provides pharmaceutical compositions and methods of treating disorders associated with uric acid, such as hyperuricemia.
A recombinant bacterial cell comprising a heterologous gene sequence encoding a uric acid catabolism enzyme operably linked to a first promoter that is not associated with the gene encoding the uric acid catabolism enzyme in nature.
The recombinant bacterial cell of any one of the previous claims, further comprising a second heterologous gene sequence encoding a second uric acid catabolism enzyme operably linked to a promoter that is not associated with the gene encoding the second uric acid catabolism enzyme in nature.
The recombinant bacterial cell of any one of the previous claims, further comprising a heterologous gene encoding a urate importer.
The recombinant bacterial cell of any one of the previous claims, wherein the first promoter is an inducible promoter.
The recombinant bacterial cell of any one of the previous claims, wherein the heterologous gene encoding the uric acid catabolism enzyme is located on a plasmid or a chromosome in the bacterial cell.
The recombinant bacterial cell of any one of the previous claims, wherein the recombinant bacterial cell is a recombinant probiotic bacterial cell.
The recombinant bacterial cell of any one of the previous claims, wherein the recombinant bacterial cell is an auxotroph in a gene that is complemented when the recombinant bacterial cell is present in a mammalian gut.
The recombinant bacterial cell of any one of the previous claims, further comprising at least one gene sequence encoding at least one enzyme of an adenosine consumption pathway.
The recombinant bacterial cell of any one of the previous claims, wherein the cell is capable of reducing levels of uric acid in vitro cell culture by at least about 60%, at least about 65%, at least about 70%, at least about 80%, or at least about 85% in about 30 minutes.
The recombinant bacterial cell of any one of the previous claims, wherein the cell is capable of reducing levels of uric acid in vitro cell culture by at least about 90%, at least about 95%, or at least about 100% in about 90 minutes.
A pharmaceutical composition comprising the recombinant bacterial cell of any one of the previous claims and a pharmaceutically acceptable carrier.
A method for treating a disease associated with uric acid in a subject, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a non-engineered bacterial cell and a pharmaceutically acceptable carrier, wherein the non-engineered bacterial cell is E. coli Nissle.
A method for reducing a level of uric acid in a subject, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a non-engineered bacterial cell and a pharmaceutically acceptable carrier, wherein the non-engineered bacterial cell is E. coli Nissle.
Dependencies are inferred from the claim text.