5-2007-42

Non-invasive Diagnostics for Liver Diseases

The Technology

The human asialoglycoprotein receptor (ASGPR) is expressed on the sinusoidal membrane of hepatocytes and serves in the clearance of asialoglycoproteins from the plasma. A soluble form of the ASGPR, termed sH2a, is formed by cleavage in the endoplasmic reticulum of its precursor. In healthy humans, sH2a is secreted to the serum at surprisingly constant levels.  sH2a levels in the serum are dramatically decreases in hepatitis C virus (HCV) patients with liver cirrhosis.  Therefore sH2a, can be a marker of liver function, correlating to the mass of functional hepatocytes. Reduction of the levels of sH2a reflects early events in the fibrogenic process, affecting hepatocyte function with the potential to become a noninvasive diagnosis of liver disease.

An ELISA assay was developed with specific monoclonal antibodies that confirmed the correlation between reduced soluble ASGPR levels and liver fibrosis, cirrhosis and carcinoma. 

The Need

Currently there is no reliable serum marker for liver disease. Liver damage is commonly associated with alcoholism, obesity and hepatitis B and C infection, which are rapidly rising worldwide. Currently, liver biopsies are the gold standard method for diagnosis of liver disease; hence the great need for a reliable non-invasive marker.

Potential Applications

Diagnosis and monitoring of:

  • Early and late stage of fibrosis of the liver
  • Monitoring success/failure in the treatment of liver fibrosis
  • Monitoring success/failure in liver transplantations
  • Liver Function – highly sensitive marker for liver function which is not influenced by clinical processes such as inflammation

Advantages

Non-invasive – liver biopsies are the gold standard method for diagnosis of liver disease, hence the great importance and market need for a reliable non-invasive marker;

Current markers (prothrombin time, albumin, etc.) can only detect liver dysfunction in advanced disease, while our novel specific marker can predict early stage fibrosis as well as probability of the treatment outcome

While enzymes such as ALT, AST, and GGT are indicators of liver damage, our novel marker serves as an indicator for liver viability

Specificity – while ALT, AST, GGT show normal blood levels in many cases of liver disease or abnormal blood levels in a wide range of non-hepatic diseases our marker is secreted exclusively by hepatocytes and thus it is a liver-specific marker. 

Stage of Development

The essential components for a non-invasive diagnostic kit for liver disease are in place. Monoclonal antibodies to soluble ASGPR have enabled development of an ELISA assay to measure serum levels of soluble ASGPR in patients and normal individuals. Recombinant soluble ASGPR was generated to validate the assay and quantify soluble ASGPR levels in sera. The method has been tested on multiple samples from men and women of varying ages, confirming the constant level of expression of soluble ASGPR in the healthy population. Fresh, frozen/thawed sera and plasma samples were compared confirming the validity of analyzing frozen samples Retrospective double blind studies were performed on blood samples from patients with liver fibrosis vs. blood samples of healthy individuals:

Analysis of ~300 samples from about 20 HCV patients with mild fibrosis were followed up before, during and after treatment for a year or longer demonstrated that the marker can (i) detect mild fibrosis and (ii) the marker is associated with liver cell viability and not with cell death, Therefore it is a highly sensitive marker for Liver Function as it is not influenced by other clinical processes such as inflammation etc.

Analysis of 43 samples from METAVIR-staged HCV patients vs. 63 samples from healthy individuals revealed that the marker can predict fibrosis stage.

A simple algorithm combining sH2a levels with those of alanine aminotransferase allowed prediction of fibrosis stage, with a very high area under the ROC curve of 0.86.

Patent

Granted US

References

J Biol Chem, 1996. 271(24): p. 14496-14503.

World J Gastroenterol. 2011 Dec 28;17(48):5305-9

PLoS One. 2011;6(11):e27210. Epub 2011 Nov 11.

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