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Application of FAK (focal adhesion kinase) inhibitor in treatment of autosomal dominant polycystic kidney disease

A dominant inheritance, autosomal technology, applied in urinary system diseases, organic active ingredients, medical preparations containing active ingredients, etc.

Pending Publication Date: 2019-09-06
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is currently no effective treatment for ADPKD, except for end-stage renal failure, which mainly relies on dialysis or kidney transplantation.

Method used

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  • Application of FAK (focal adhesion kinase) inhibitor in treatment of autosomal dominant polycystic kidney disease
  • Application of FAK (focal adhesion kinase) inhibitor in treatment of autosomal dominant polycystic kidney disease
  • Application of FAK (focal adhesion kinase) inhibitor in treatment of autosomal dominant polycystic kidney disease

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Vesicle growth inhibition experiments were performed.

[0037]Canine kidney cells (Madin-Darby canine kidney cells, MDCK) were cultured in three-dimensional Matrigel (Purecol Collagen, Inamed Biomaterials Fremont Company, Cat. No. 5409) in vitro. The culture medium 1 used was to add three-dimensional Matrigel, HEPES, penicillin and streptomycin obtained the three-dimensional matrigel concentration of 2.9mg / ml, HEPES concentration of 10mM, penicillin concentration of 100U / ml, streptomycin concentration of 100μg / ml culture solution, pH 7.4. Culture solution 2 is a culture solution with FBS concentration of 10% and forskolin concentration of 10 μM by adding FBS and forskolin (FSK, forskolin, Sigma company, product number F6886) to DMEM / F12 culture solution. DMEM / F12 culture solution It is a liquid obtained by mixing equal volumes of DMEM medium (Invitrogen Company of the United States, catalog number 12100-046) and F12 medium (Invitrogen Company of the United States, catal...

Embodiment 2

[0040] In the evening of the first day, C57BL / 6 mice over 6 weeks old (Experimental Animal Center, Peking University Health Science Center) were mated with males and females in the same cage at a ratio of 1:1. The plug indicates that the female mouse has been pregnant for half a day. The mice without the vaginal plug are divided into cages first, and then closed in the cage at night, and then observed on the second day; the pregnant female mice are fed alone for 13 days, and the transwell plate is used for the embryonic kidney on the 13th day (Corning Company, Cat. No. 3401) for cultivation.

[0041] The 13.5-day-old mouse embryonic kidney was taken and placed in the upper chamber of the transwell, and DMEM culture solution containing 8-Br-cAMP (Sigma Company, product number B-5386) with a final concentration of 100 μM was added to the lower culture well for cultivation. Under the action of cAMP, multiple and progressively growing renal vesicles will be formed in the kidney ti...

Embodiment 3

[0044] The mice used were obtained as follows: the Pkd1 flox / flox Mating of mice and Ksp-Cre mice to obtain a generation of Pkd1 + / - ; Ksp-Cre mice, Pkd1 + / - ; Male mice and female mice of Ksp-Cre mice were mated to obtain wild-type mice Pkd1 + / + ; Ksp-Cre and Pkd1 flox / flox ; Ksp-Cre mice (PKD mice). Among them, Pkd1 flox / flox The genetic backgrounds of mice and Ksp-Cre mice are both C57BL / 6 mice, both of which are recorded in the literature (...Wang W, Li F, Sun Y, et al. Aquaporin-1 retards renal cyst development in polycystic kidney disease by inhibition ofWnt signaling. FASEB J. 2015;29(4):1551-1563.). Pkd1 flox / flox The mice are mice obtained by knocking out the Pkd1 gene specifically for the whole kidney in the background of C57BL / 6 mice, so that the mice will develop rapidly progressive ADPKD after birth, and the mice can survive for about 7 years after birth. -About 10 days, genetic identification is carried out on the first day after the birth of the mouse to ...

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Abstract

The invention proves, through the application of an MDCK (Madin-Darby canine kidney cells) vesicular model, that an FAK (focal adhesion kinase) inhibitor can inhibit the generation and growth of vesicles, can determine intrarenal pharmacological activity of the FAK inhibitor through an in-vitro embryonal vesicular model, and can inhibit the progress of intrarenal vesicles significantly. The invention further proves finally, in a polycystic renal mouse model, that the FAK inhibitor can also inhibit the progress of vesicles in vivo, while the in-vitro and in-vivo vesicular inhibitory actions arein dose-effect relationship. The FAK inhibitor never affects the activity of renal cells; it is indicated that the ability of the FAK inhibitor to polycystic kidney is irrelevant to its cytotoxicity,and that the FAK inhibitor can regulate intracellular signal pathways, which may be one of its important mechanisms to inhibit the progress of renal vesicles. The FAK inhibitor is VS4718 which is suitable for treating autosomal dominant polycystic kidney disease.

Description

technical field [0001] The invention belongs to the field of biotechnology, and in particular relates to the application of a focal adhesion kinase inhibitor, that is, a FAK inhibitor, in the treatment of autosomal dominant polycystic kidney disease. Background technique [0002] Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic hereditary disease with an incidence rate of about 1 / 1000-1 / 400, ranking first among hereditary kidney diseases. ADPKD is characterized by multiple progressive fluid-filled vesicles in bilateral kidneys, excessive proliferation of vesicular epithelial cells, abnormal secretion of cyst fluid, and interstitial fibrosis. The gradually enlarged fluid-filled vesicles constantly squeeze the surrounding normal kidney tissue, leading to the destruction of normal kidney structure and loss of function, and eventually develop into end-stage renal failure (ESRF). The fourth cause of renal failure. Patients with ADPKD usually experience...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/444A61P13/12
CPCA61K31/444A61K45/00A61P13/12
Inventor 周虹杨宝学贺巾钊
Owner PEKING UNIV
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