# US 11,078,259 B2 · Methods and compositions for promoting thermogenic potential

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- Number: US 11,078,259 B2
- Document ID: US11078259B2
- Status: Granted
- Kind: B2
- Application number: 15/579,885
- Filed: 2016-06-03
- Published: 2018-12-20
- Granted: 2021-08-03
- Earliest claimed: 2015-06-05
- Assignees: Joslin Diabetes Center, Inc.
- Applicants: Joslin Diabetes Center, Inc.
- Inventors: Yu-Hua Tseng; Matthew Lynes; Ruidan Xue
- Web page: https://patentgrep.com/patent/US11078259B2

## CPC

- C07K 16/18: against material from animals or humans
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 35/35: Fat tissue; Adipocytes; Stromal cells; Connective tissues (adipose-derived stem cells A61K35/28; collagen A61K38/39)
- A61K 35/545: Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
- A61K 38/1719: {Muscle proteins, e.g. myosin or actin}
- A61K 38/1761: {Apoptosis related proteins, e.g. Apoptotic protease-activating factor-1 (APAF-1), Bax, Bax-inhibitory protein(s)(BI; bax-I), Myeloid cell leukemia associated protein (MCL-1), Inhibitor of apoptosis [IAP] or Bcl-2}
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61K 38/1796: {for hormones (for neuromediators A61K38/1787)}
- A61K 38/465: {acting on ester bonds (3.1), e.g. lipases, ribonucleases}
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- C12N 5/0653: {Adipocytes; Adipose tissue}
- C12N 15/11: DNA or RNA fragments; Modified forms thereof (DNA or RNA not used in recombinant technology, C07H21/00); {Non-coding nucleic acids having a biological activity}
- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Y 301/03048: Protein-tyrosine-phosphatase (3.1.3.48)
- G01N 33/5091: {for testing the pathological state of an organism}
- C07K 2317/75: Agonist effect on antigen
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C12N 9/224: {Class 1 CAS enzyme complex, e.g. multi-enzyme}
- C12N 2800/80: Vectors containing sites for inducing double-stranded breaks, e.g. meganuclease restriction sites
- C12Q 2600/118: Prognosis of disease development
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Y: ENZYMES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The invention provides methods and compositions relating to molecular targets identified as being capable of increasing or decreasing thermogenic potential in cells, including preadipocytes. Included in the invention are methods and compositions relating to inhibiting or suppressing the activity of an uncoupling protein 1 (UCP1) negative regulator, such as cardiac actin 1 (ACTC1), somatostatin receptor 1 (SSTR1), FAT atypical cadherin 1 (FAT1), and protein tyrosine phosphatase receptor type B (PTPRB). Also included in the invention are methods and compositions relating to activating a UCP1 positive regulator, such as phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 1 (PREX1), cortactin binding protein 2 (CTTNBP2), doublesex and mab-3-related transcription factor-like family A1 (DMRTA1), and endothelin receptor type B (ENDRB). The invention also provides methods and compositions relating to enrichment of cells having thermogenic potential based on cell surface markers, e.g., CD29, identified as being predictive of such.

## Claims

### Claim 1

A method of promoting thermogenic capacity in a thermogenically competent cell, the method comprising contacting the thermogenically competent cell with either an activator of a uncoupling protein 1 (UCP1) positive regulator or a UCP1 positive regulator, such that thermogenic capacity is promoted, wherein the UCP1 positive regulator is selected from the group consisting of phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 1 (PREX1), cortactin binding protein 2 (CTTNBP2), doublesex and mab-3-related transcription factor-like family A1 (DMRTA1) and endothelin receptor type B (EDNRB), or combinations thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the thermogenically competent cell is contacted with either
a) an agonist antibody, or antigen-binding fragment thereof, that binds the UCP1 positive regulator;
b) the UCP1 positive regulator;
c) a nucleic acid molecule encoding the UCP1 positive regulator, or
d) a polynucleotide associated with the CRISPR/Cas system which binds the UCP1 positive regulator and activates the transcription of the UCP1 positive regulator.

### Claim 3 (depends on 1)

The method of claim 1, wherein the activator of a UCP1 positive regulator is either an agonist antibody, or antigen-binding fragment thereof, that binds the UCP1 positive regulator, or a polynucleotide associated with the CRISPR/Cas system which binds the UCP1 positive regulator and activates the transcription of the UCP1 positive regulator.

### Claim 4

A method of treating a human subject having obesity, said method comprising administering a therapeutically effective amount of
(1) an activator of a UCP1 positive regulator to the human subject, wherein the UCP1 positive regulator is selected from the group consisting of human PREX1, human CTTNBP2, human DMRTA1, and human EDNRB, or
(2) a UCP1 positive regulator to the human subject, wherein the UCP1 positive regulator is selected from the group consisting of human PREX1, human CTTNBP2, human DMRTA1, and human EDNRB,
such that the obesity is treated.

### Claim 5

A method of decreasing the weight of a human subject, said method comprising administering a therapeutically effective amount of
(1) an activator of a UCP1 positive regulator to the human subject, wherein the UCP1 positive regulator is selected from the group consisting of human PREX1, human CTTNBP2, human DMRTA1, and human EDNRB, or
(2) a UCP1 positive regulator to the human subject, wherein the UCP1 positive regulator is selected from the group consisting of human PREX1, human CTTNBP2, human DMRTA1, and human EDNRB,
such that the weight of the human subject is decreased.