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Hip/pap polypeptide compositions for use in liver regeneration and for the prevention of liver failure

a technology of liver failure and composition, applied in the field of human hepatocarcinomaintestinepancreas/pancreaticassociated protein, can solve the problems of liver failure risk of patients subject to inborn metabolism errors, severe damage to body's entire metabolism, and metabolic instability, so as to improve liver function and liver function, and confirm liver cell transplantation

Inactive Publication Date: 2006-12-07
INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM) +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is based on the discovery that a specific polypeptide called HIP / PAP has beneficial effects on liver cells in both in vitro and in vivo experiments. It can stimulate liver regeneration and prevent cell death during liver failure or regeneration. The invention is also about a pharmaceutical composition containing this polypeptide and a physiologically acceptable excipient. Additionally, the invention includes a pharmaceutical composition with limited adverse effects on liver necrosis, which includes a therapeutically effective amount of a hepatotoxic compound and a liver damage effective amount of the polypeptide.

Problems solved by technology

In addition, patients subject to inborn errors of metabolism may be at risk for developing liver failure.
If the disease progresses beyond the liver's capacity to regenerate new cells, the body's entire metabolism is severely affected.
Loss of liver function may result in metabolic instability combined with disruption of essential bodily functions (i.e., energy supply, acid-base balance and thermoregulation.)
If not rapidly reversed, complications such as uncontrolled bleeding and sepsis occur, and dependent organs such as the brain and kidneys cease to function because of toxic byproducts or because the liver is no longer synthesizing important nutrients.
However, the clinical application of liver transplantation is limited by the availability of human hepatocytes, liver tissue and the number of liver cells that can be transplanted safely at one time.
Liver resections performed on patients with extrahepatic disease may relieve the symptoms caused by the tumor, but offer little improvement in survival.
Liver cell is believed to be controlled by various growth stimulatory and growth inhibitory cytokines of autocrine or paracrine origin, however, the exact role and action mechanism of these growth factors is far from entirely understood.
However, these therapeutic strategies, suggested to stimulate liver regeneration and suppress liver failure, have not proved their efficacity without toxicity, and adverse effects.
However, partial liver transplantation cannot be considered as a safe operation for adults representing the majority of transplantation patients because the resectable liver weight of donors is often less than the necessary liver weight for recipients.

Method used

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  • Hip/pap polypeptide compositions for use in liver regeneration and for the prevention of liver failure
  • Hip/pap polypeptide compositions for use in liver regeneration and for the prevention of liver failure
  • Hip/pap polypeptide compositions for use in liver regeneration and for the prevention of liver failure

Examples

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example 1

Characterization of Human HIP / PAP Transgenic Mice

[0218] The HIP / PAP transgene was specifically expressed in the liver, and HIP / PAP-expressing mice did not develop livers tumours, after a two year following. Immunohistolocalization analysis detected HIP / PAP protein in the liver of transgenic mice as diffuse intra-hepatocyte immunostaining, occupying most of the cytoplasm of the hepatocytes (FIGS. 2A, 1 and 2). Staining was heterogenous and positive regions were located either in centrolobular or portal areas of the liver acinus. This heterogeneous distribution likely reflects HIP / PAP secretion, thus hepatocytes could be either positive or negative before or after HIP / PAP secretion respectively. HIP / PAP protein was secreted into the serum (250 ng / ml to 700 ng / ml) in homozygote transgenic lines 24 and 27, and into the culture medium of primary hepatocytes (30 to 120 ng / ml per 2.105 cells). No difference in morphology and ploïdy was detected between HIP / PAP-expressing and control hepat...

example 2

Liver Regeneration is Stimulated in Mice Expressing the Human HIP / PAP Gene

[0219] To test in vivo the HIP / PAP effect on liver cell proliferation, liver regeneration induced by partial hepatectomy was examined. Low magnification (×20) views for times 24, 36, 46 and 55 hours post partial hepatectomy are presented FIG. 3A. At the indicated times, percentages of positive BrdU cells were higher in HIP / PAP transgenic than in wild-type livers, despite the low overall frequency of nuclei which had incorporated BrdU in both groups. The percentages of nuclei incorporating BrdU were significantly higher in HIP / PAP transgenic mice (median 33%; range 20-42%) compared to wild-type (median 18%; range 11-27%) (P=0.0014), 46 hours after partial hepatectomy (FIG. 3 B). To reinforce the hypothesis that HIP / PAP protein may act as Growth Factor during liver regeneration, the time-course of the hepatic mass restoration in wild-type and transgenic mice was established, after hepatectomy (FIG. 3C). Animal ...

example 3

HIP / PAP Mitogenic Effect in Primary Culture Hepatocytes

[0220] In order to further investigate the enhanced liver regeneration observed in vivo after hepatectomy in HIP / PAP transgenic mice, primary cultures of hepatocytes were used to evaluate a HIP / PAP mitogenic effect. Hepatocytes derived from HIP / PAP transgenic and wild-type mice exhibited two peaks DNA synthesis, 60 and 84 hours after plating, when stimulated by EGF (FIGS. 4 A and B). At 60 hours, mean percentages of BrdU-positive hepatocytes were 31±7% (n=19) and 16±4% (n=20) in transgenic and wild-type mice, respectively (p−1) was added to wild-type hepatocytes, EGF-induced DNA synthesis increased from 16±4% to 24±7% (p=0.0168; n=8; FIG. 4C). These results showed that HIP / PAP was a mitogenic factor for hepatocytes in primary culture. The mitogenic effect of HIP / PAP on hepatocyte proliferation was thus demonstrated both in vivo and in vitro.

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Abstract

This invention is based on the experimental finding that HIP / PAP has mitogenic and antiapoptotic effects in vitro on hepatocytes in primary culture. Moreover, HIP / PAP is a mitogenic and anti-apoptotic molecule for hepatocytes, in vivo, during liver failure and liver regeneration. The present invention is also based on the experimental finding that HIP / PAP administration has no adverse effects in mammals. This invention concerns a pharmaceutical composition for stimulating liver regeneration in vivo including after chronic / acute liver failure, comprising an effective amount of a polypeptide comprising an amino acid sequence having 90% amino acid identity with the polypeptide consisting of the amino acid sequence starting at the amino acid residue (36) and ending at the amino acid residue (175) of sequence SEQ ID No. 1, in combination with at least one physiologically acceptable excipient.

Description

FIELD OF THE INVENTION [0001] The present invention concerns the use of the human hepatocarcinoma-intestine-pancreas / pancreatic-associated protein (HIP / PAP) for stimulating liver regeneration and also for the prevention of liver failure. BACKGROUND ART [0002] Liver failure occurs in a number of acute and chronic clinical conditions, including drug-induced hepatotoxicity, viral infections, vascular injury, autoimmune disease, or blunts trauma. In addition, patients subject to inborn errors of metabolism may be at risk for developing liver failure. Symptoms of liver failure occurring as a result of these clinical conditions include, for example, fulminant acute hepatitis, chronic hepatitis, or cirrhosis, and in many instances, the restoration of normal liver function is vital to the survival of patients. For example, cirrhosis is the seventh leading cause of death and the fourth disease related cause of death in people between the ages of 25 to 44. (Source: American Liver Foundation)....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17A61P1/16C12N5/07C12N5/074
CPCA61K38/1709A61P1/00A61P1/16A61P13/02A61P25/00A61P3/00A61P35/00A61P3/06A61P37/02A61P43/00A61P7/00A61P9/00
Inventor CHRISTA, LAURENCEBRECHOT, CHRISTIANSIMON-GAGE-SOUFFLOT, MARIE-THERESEPAULOIN, ALAINGUILHERME TRALHAO, J.
Owner INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)
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