# US 11,896,627 B2 · Bacteria engineered to treat metabolic diseases

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- Number: US 11,896,627 B2
- Document ID: US11896627B2
- Status: Granted
- Kind: B2
- Application number: 17/584,956
- Filed: 2022-01-26
- Published: 2022-07-21
- Granted: 2024-02-13
- Earliest claimed: 2015-06-25
- Assignees: Synlogic Operating Company, Inc.
- Applicants: Synlogic Operating Company, Inc.
- Inventors: Dean Falb; Vincent M. Isabella; Jonathan W. Kotula; Paul F. Miller; Sarah Elizabeth Rowe; Yves Millet; Adam B. Fisher
- Web page: https://patentgrep.com/patent/US11896627B2

## CPC

- A61K 35/74: Bacteria (therapeutic use of a bacterial protein A61K38/00)
- A23L 33/135: Bacteria or derivatives thereof, e.g. probiotics
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 35/741: Probiotics (probiotic yeast, e.g. saccharomyces A61K36/06)
- A61K 35/744: Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K 35/745: Bifidobacteria
- A61K 35/747: Lactobacilli, e.g. L. acidophilus or L. brevis
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C12N 15/52: Genes encoding for enzymes or proenzymes
- A23V 2002/00: Food compositions, function of food ingredients or processes for food or foodstuffs
- A61K 9/0031: {Rectum, anus}
- A61K 2035/115: {Probiotics}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A23L: FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF (preservation thereof A23B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A23V: INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Genetically engineered bacteria, pharmaceutical compositions thereof, and methods of attenuating metabolic diseases are disclosed.

## Claims

### Claim 1

A bacterium comprising a gene cassette that encodes a biosynthetic pathway for producing a short chain fatty acid, wherein the short chain fatty acid is butyrate, propionate, or acetate, and wherein the gene cassette is operably linked to a promoter that is induced by exogenous environmental conditions found in a mammalian gut and that is not associated with the gene cassette in nature, and wherein the bacterium further comprises a gene or gene cassette for producing indole-3-acetaldehyde.

### Claim 2 (depends on 1)

The bacterium of claim 1, wherein the short chain fatty acid is butyrate.

### Claim 3 (depends on 1)

The bacterium of claim 1, wherein the promoter is induced by low-oxygen or anaerobic conditions.

### Claim 4 (depends on 3)

The bacterium of claim 3, wherein the promoter is selected from a fumarate and nitrate reductase regulator (FNR)-inducible promoter, an arginine deiminiase and nitrate reduction transcriptional regulator (ANR)-inducible promoter, and a dissimilatory nitrate respiration regulator (DNR)-inducible promoter, reactive nitrogen species (RNS)-induced promoter, and reactive oxygen species (ROS)-induced promoter.

### Claim 5 (depends on 4)

The bacterium of claim 4, wherein the promoter is a FNR-inducible promoter.

### Claim 6 (depends on 4)

The bacterium of claim 4, wherein the gene cassette and operatively linked promoter are present on a plasmid in the bacterium.

### Claim 7 (depends on 4)

The bacterium of claim 4, wherein the gene cassette and operatively linked promoter are present on a chromosome in the bacterium.

### Claim 8 (depends on 1)

The bacterium of claim 1, wherein the bacterium is an auxotroph comprising a deletion or mutation in a gene required for cell survival and/or growth.

### Claim 9 (depends on 8)

The bacterium of claim 8, wherein the bacterium is an auxotroph in diaminopimelic acid or an enzyme in the thymidine biosynthetic pathway.

### Claim 10 (depends on 1)

The bacterium of claim 1, wherein the bacterium comprises a kill switch.

### Claim 11 (depends on 1)

The bacterium of claim 1, wherein the bacterium further comprises a second gene encoding a substance toxic to the bacterium, wherein the second gene is under the control of a second promoter that is directly or indirectly induced by an exogenous environmental condition not naturally present in a mammalian gut.

### Claim 12 (depends on 1)

The bacterium of claim 1, wherein the bacterium is a non-pathogenic bacterium.

### Claim 13 (depends on 1)

The bacterium of claim 1, wherein the bacterium is a probiotic or a commensal bacterium.

### Claim 14 (depends on 13)

The bacterium of claim 13, wherein the bacterium is selected from the group consisting of Bacteroides, Bifidobacterium, Clostridium, Escherichia, Lactobacillus, and Lactococcus.

### Claim 15 (depends on 1)

The bacterium of claim 1, wherein the bacterium comprises a knockout in a clb gene.

### Claim 16 (depends on 14)

The bacterium of claim 14, wherein the bacterium is Escherichia coli strain Nissle.

### Claim 17 (depends on 1)

A pharmaceutically acceptable composition comprising the bacterium of claim 1, and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 17)

The pharmaceutically acceptable composition of claim 17, wherein the composition is formulated for oral administration.

### Claim 19 (depends on 17)

The pharmaceutically acceptable composition of claim 17, wherein the composition is for use in treating a metabolic disease or disorder.

### Claim 20 (depends on 18)

The pharmaceutically acceptable composition of claim 18, wherein the composition is for use in treating a metabolic disease or disorder.

### Claim 21 (depends on 19)

The pharmaceutically acceptable composition of claim 19, wherein the metabolic disease or disorder is selected for the group consisting of type 1 diabetes; type 2 diabetes; metabolic syndrome; Bardet-Biedel syndrome; Prader-Willi syndrome; non-alcoholic fatty liver disease; tuberous sclerosis; Albright hereditary osteodystrophy; brain-derived neurotrophic factor (BDNF) deficiency; Single-minded 1 (SIM1) deficiency; leptin deficiency; leptin receptor deficiency; pro-opiomelanocortin (POMC) defects; proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency; Src homology 2B1 (SH2B1) deficiency; pro-hormone convertase 1/3 deficiency; melanocortin-4-receptor (MC4R) deficiency; Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome; pseudohypoparathyroidism type 1A; Fragile X syndrome; Borjeson-Forsmann-Lehmann syndrome; Alstrom syndrome; Cohen syndrome; and ulnar-mammary syndrome.

### Claim 22 (depends on 21)

The pharmaceutically acceptable composition of claim 21, wherein the metabolic disease or disorder is type 1 diabetes or type 2 diabetes.