# US 7,919,673 B2 · Transgenic pig with altered incretin function

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- Number: US 7,919,673 B2
- Document ID: US7919673B2
- Status: Granted
- Kind: B2
- Application number: 12/348,294
- Filed: 2009-01-04
- Published: 2009-09-10
- Granted: 2011-04-05
- Earliest claimed: 2008-01-04
- Assignees: Ludwig-Maximilians-Universitat; MWM Biomodels GmbH
- Inventors: Eckhard Wolf; Simone Renner; Barbara Kessler; Rüdiger Wanke; Nadja Herbach; Alexander Pfeifer; Andreas Hofmann
- Web page: https://patentgrep.com/patent/US7919673B2

## CPC

- C07K 14/723: {G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH receptor}
- A01K 67/0276: Knock-out vertebrates
- G01N 33/507: {Pancreatic cells}
- A01K 2217/056: due to mutation of coding region of the transgene (dominant negative)
- A01K 2227/108: Swine
- A01K 2267/0362: Animal model for lipid/glucose metabolism, e.g. obesity, type-2 diabetes
- C12N 2799/027: where the vector is derived from a retrovirus
- G01N 2500/10: involving cells
- G01N 2800/042: Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
- 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)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention relates to transgenic pigs containing a dominant-negative incretin hormone receptor, namely the dominant-negative human glucose-dependent insulinotropic polypeptide receptor. The present invention furthermore relates to uses of these transgenic pigs as clinically relevant animal model systems for studying the pathogenesis and novel therapies for diabetes mellitus type 2, particularly for the maintenance and expansion of pancreatic β-cell mass.

## Claims

### Claim 1

A transgenic pig whose genome comprises a recombinant nucleic acid encoding a dominant-negative human glucose-dependent insulinotropic polypeptide receptor (GIPRdn) operably linked to an insulin promoter that results in expression of the dominant-negative human glucose-dependent insulinotropic polypeptide receptor (GIPRdn), wherein said pig expresses the dominant-negative human glucose-dependent insulinotropic polypeptide receptor (GIPRdn), and wherein said pig exhibits, as a result of the expression of said receptor, at least one of:
a) an elevated glucose level following an oral glucose load;
b) reduced or delayed insulin secretion;
c) reduced oral glucose tolerance;
d) reduced pancreatic islet and β-cell mass; and
e) impaired glucose-dependent insulinotropic polypeptide (GIP) function.

### Claim 2 (depends on 1)

The transgenic pig, according to claim 1, wherein the recombinant nucleic acid is a plasmid or viral vector.

### Claim 3 (depends on 2)

The transgenic pig, according to claim 2, wherein the recombinant nucleic acid is a lentiviral vector.

### Claim 4 (depends on 3)

The transgenic pig, according to claim 3, wherein the recombinant nucleic acid is a lentiviral vector comprising rat insulin 2 gene promoter (RIPII) or pig INS promoter.

### Claim 5 (depends on 1)

The transgenic pig, according to claim 1, wherein the recombinant nucleic acid encodes a protein which comprises an amino acid sequence identical to SEQ ID NO:1 except that said amino acid sequence has an amino acid change at residue 332 of SEQ ID NO:1 in the third intracellular loop of the hGIPR, wherein residue 332 of said amino acid sequence is not Ala.

### Claim 6 (depends on 1)

The transgenic pig, according to claim 1, wherein the recombinant nucleic acid encodes a protein which has the sequence of SEQ ID NO: 1.

### Claim 7 (depends on 1)

The transgenic pig, according to claim 1, wherein the recombinant nucleic acid comprises a sequence having SEQ ID NO: 2.

### Claim 8 (depends on 1)

The transgenic pig, according to claim 1, containing the recombinant nucleic acid in its germ cells and somatic cells.

### Claim 9 (depends on 1)

The transgenic pig, according to claim 1, wherein hGIPRdn is expressed in the islets of the pancreas.

### Claim 10 (depends on 9)

The transgenic pig, according to claim 9, wherein the hGIPRdn is expressed in the β-cells.

### Claim 11 (depends on 1)

The transgenic pig, according to claim 1, wherein pancreatic islet and β-cell mass is reduced.