# US 10,307,461 B2 · Method of preventing polycystic kidney disease and PKD animal model with exogenous neutrophil gelatinase-associated lipocalin

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- Number: US 10,307,461 B2
- Document ID: US10307461B2
- Status: Granted
- Kind: B2
- Application number: 15/220,687
- Filed: 2016-07-27
- Published: 2017-06-29
- Granted: 2019-06-04
- Earliest claimed: 2015-12-23
- Assignees: National Taiwan Normal University
- Applicants: National Taiwan Normal University
- Inventors: Hsiu-Mei Hsieh; Yi-Ren Wang; Si-Tse Jiang; Wen-Yih Jeng; Yuan-Yow Chiou
- Web page: https://patentgrep.com/patent/US10307461B2

## CPC

- A61K 38/1709: {from mammals}
- A61K 38/16: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)}
- A61P 13/12: of the kidneys
- C07K 14/47: from mammals
- A01K 67/0275: Genetically modified vertebrates, e.g. transgenic
- A01K 67/0276: Knock-out vertebrates
- A01K 2217/075: inducing loss of function, i.e. knock out
- A01K 2227/105: Murine
- A01K 2267/0306: Animal model for genetic diseases
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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

## Abstract

Disclosed is a method of treating or preventing polycystic kidney disease (PKD) by administration of neutrophil geleatinase-associated lipocalin (Ngal) protein. Also, a transgenic non-human animal model is established to investigate the effect of overexpression of exogenous Ngal on PKD progression.

## Claims

### Claim 1

A method of preventing polycystic kidney disease (PKD), comprising: administering an effective amount of neutrophil gelatinase-associated lipocalin (NGAL) to a subject in need, wherein preventing PKD is statistically significantly improving survival and lifespan of a patient through at least four of the following pathophysiological mechanisms or features: retarding renal cyst growth, reducing renal cyst volume and kidney/body weight, reducing renal interstitial fibrosis, reducing hypoxia in the interstitial compartment of kidney, increasing apoptosis of cystic epithelial cells and decreasing proliferation of cystic epithelial cells in the kidney;
wherein the PKD is autosomal dominant polycystic kidney disease (ADPKD), and administering the effective amount of neutrophil gelatinase-associated lipocalin (NGAL) is before statistically significant ischemic injury.

### Claim 2 (depends on 1)

The method of claim 1, wherein the NGAL induces at least one of the following: increased expression of NGAL and NGAL receptor (NGAL-R), increased active-caspase-3 and decreased pro-caspase 3 in preventing PKD.

### Claim 3 (depends on 1)

The method of claim 1, wherein the NGAL inhibits the expression of at least one of: α-SMA, collagen, hypoxia-inducible factor 1-α (HIF-1α), pro-caspase 3, proliferating cell nuclear antigen (PCNA), Akt, mammalian target of rapamycin (mTOR) and S6K in preventing PKD.

### Claim 4 (depends on 1)

The method of claim 1, wherein the NGAL is dose-dependent.

### Claim 5 (depends on 1)

The method of claim 1, wherein the NGAL induces at least four of the following: reduced α-SMA, reduced hypoxia-inducible factor 1-α (HIF-1α), reduced Akt, reduced mammalian target of rapamycin (mTOR), reduced S6K, reduced pro-caspase 3, reduced proliferating cell nuclear antigen (PCNA), increased expression of NGAL and NGAL receptor (NGAL-R), and increased active-caspase-3 in preventing PKD.