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Use of human Zven proteins and polynucleotides

a technology of which is applied in the field of human zven proteins and polynucleotides, can solve the problems of increased medical costs, increased medical costs, and possible other complications, and abnormal gastric emptying

Inactive Publication Date: 2007-03-01
ZYMOGENETICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Gastric emptying is frequently abnormal in patients with critical illness or who are recovering from surgery.
It is especially problematic following abdominal surgery.
The problem may arise from the surgery itself, from the residual effects of anesthetic agents, and particularly, from pain-relieving narcotic and opiate drugs used during and after surgery.
Thus, patients undergoing abdominal surgery who have a delay in recovery of gastrointestinal function have prolonged hospital stays, which can lead to increased medical costs and potentially to other complications.
Currently there are no drugs that have been approved for treatment of this disease.
Since up to two-thirds of individuals with diabetes suffer from some degree of gastroparesis, this problem is significant.
Moreover, symptoms associated with diabetic gastroparesis, such as delayed gastric emptying, and emesis can cause water and electrolyte imbalances, poor glycemic control, and ensuing complications.
Currently there are very few drugs that can effectively treat diabetic gastroparesis, and those that are available have side effects and / or cannot be taken with other medications.
Oral drugs may not be tolerated during severe episodes, and thus, would require intravenous administration of a prokinetic.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Stimulation of Responses in Wky12-22 Cells

[0368] Wky12-22 cells were derived from the medial layer of the thoracic aorta of Wistar-Kyoto rat pups, as described by Lemire et al., American Journal of Patholog 144:1068 (1994). These cells respond to both Zven1 and Zven2 in a reporter luciferase assay following transfection with NFkB / Ap-1 reporter construct. A control cell line, Wky3M-22, derived from the same tissue in adult rat did not signal. Activity was detected at concentrations ranging from 1-100 ng / ml of Zven1 or Zven2 (approximately 0.1 nM-10 nM). These data suggest that Wky12-22 cells carry the Zven1 receptor, and that Zven1 and Zven2 activate the NfKb / Ap-1 transcription factor.

[0369] In one experiment, Wky12-22 cells were loaded with the fluorescent dye Fura. The emission peak of Fura shifts when bound to calcium. Intracellular calcium release is detected by monitoring the wavelength shift. Zven1 induced intracellular calcium release at concentrations of 1-1000 ng / ml. Zven2...

example 2

Zven1 and Zven2 Stimulate Chemokine Release In Vitro

[0373] Confluent Wky12-22 or Wky3M22 cells were incubated with varying concentrations of Zven1 for twenty-four hours. Conditioned media were collected and assayed for the chemokine CINC-1 using a commercially-available rat cytokine multiplex kit (Linco Research, Inc.; St. Charles, Mo.). CINC-1, thought to be equivalent to human growth-related oncogene-α (GRO-α), was detected at levels ranging from 1.8-5 ng / ml in cells treated with 0.1 to 100 ng / ml of Zven1 respectively. Zven2 induced an equivalent level of CINC-1 release from Wky12-22 cells. CINC-1 was not detected in either the control Wky3M-22 cell line derived from adult rat aorta, or non-treated controls.

example 3

Zven1 Induces a Chemotactic Response and Stimulates Chemokine Release and Neutrophil Infilration In Vivo

[0374] Four groups of ten mice (BALB57 / BL6 females at eight weeks of age) were either not treated, or injected with vehicle buffer control, 0.1 μg of Zven1 or 1 μg of Zven1. Four hours later, peritoneal lavage fluid was collected, concentrated, and the cell pellets were resuspended. The relative cell populations were enumerated using the Cell Dyne, and cytospins were prepared for CBC / diff counts. The non-treated and buffer control animals had approximately 2% neutrophils in their lavage fluid, while the 0.1 μg treated animals had approximately 30% neutrophils, indicating an approximate 15-fold increase in neutrophils in the peritoneum of the Zven1-treated animals. The 1 μg Zven1-treated animals had neutrophil levels consistent with the non-treated controls, suggesting a bi-phasic Zven1 response. In sum, Zven1 induced neutrophil infiltration into the peritoneum following intraperi...

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Abstract

The present invention provides methods of using Zven1 and Zven2 polypeptides to increase chemokine production. The present invention also provides methods for treating intestinal motility disorders and improving gastrointestinal function with Zven1 and Zven2 polypeptides.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. application Ser. No. 10 / 680,800, filed Oct. 7, 2003, which claims the benefit of U.S. Provisional Application Ser. No. 60 / 416,719, filed Oct. 7, 2002; U.S. Provisional Application Ser. No. 60 / 416,718, filed Oct. 7, 2002; U.S. Provisional Application Ser. No. 60 / 434,116, filed Dec. 16, 2002; U.S. Provisional Application Ser. No. 60 / 433,918, filed Dec. 16, 2002; U.S. Provisional Application Ser. No. 60 / 508,614, filed Oct. 3, 2003; and U.S. Provisional Application Ser. No. 60 / 508,603, filed Oct. 3, 2003, all of which are herein incorporated by reference.BACKGROUND OF THE INVENTION [0002] Optimal gastrointestinal function includes mixing and forward propulsion of contents in the stomach and intestine. Gastric emptying is frequently abnormal in patients with critical illness or who are recovering from surgery. Recovery of gastrointestinal function and resumption of oral intake are important determinan...

Claims

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Application Information

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IPC IPC(8): A61K38/19A61K38/00A61K38/17C07K14/47C12N5/02G01N33/68
CPCA61K38/1709C07K14/47G01N2800/065G01N33/6893G01N2800/06C07K14/4702A61P1/00A61P1/04A61P29/00A61P37/00
Inventor THOMPSON, PENNYLEWIS, KATHERINEJASPERS, STEPHENGARCIA, RICHARDWEST, ROBERTHOLDERMAN, SUSANCHAN, CHUNGSHEPPARD, PAULWOLF, ANITRA
Owner ZYMOGENETICS INC
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