Liver fibrosis determines long-term morbidity and mortality in liver disease. We explore the biology behind liver fibrosis and the need for new precision treatments in this space. 

What is liver fibrosis?

Liver fibrosis results from excessive wound healing, which leads to the build-up of too much connective tissue. As cells within the liver are signalled to produce extracellular matrix, the large amounts produced with insufficient removal form too much connective tissue. This excess connective tissue leads to a disordered architecture of the liver and is the scarring of the liver. It results from chronic injury, often with an inflammatory element.

In cases of acute injury, wound healing is dynamic and reversible. The extracellular matrix laid down by the cells is important to mechanically stabilise the injured liver tissue, and allow immune, endothelial and adult stem cells to migrate into the repairing tissue. However, when injury to the liver is repetitive, the web of extracellular matrix components continue to accumulate in the tissue and liver fibrosis occurs.

Fibrosis does not cause symptoms, but the scarring of the tissue can distort and slow the flow of blood through the liver, causing high blood pressure in the blood vessels that supply the liver – a condition known as portal hypertension. If liver fibrosis progresses to the point where scarring in the liver disrupts normal organ structure and function, it is termed cirrhosis. Liver cirrhosis is irreversible and can result in liver failure requiring liver transplantation.

Advanced liver fibrosis and cirrhosis are major risk factors for liver cancer, such as hepatocellular carcinoma.

What causes liver fibrosis?

A wide range of diseases and conditions can damage the liver and lead to fibrosis.

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, and viral hepatitis can result in liver fibrosis, cirrhosis and cancer.

At the cellular level, chronic liver injury, through disease or diet, activates resident hepatic stellate cells (HSCs). These cells are the major source of fibrous scar tissue in the liver, through overproduction of extracellular matrix. The extracellular matrix is a large network of proteins, minerals, and signalling molecules that surround cells in a tissue to support their structure and movement. While essential to the normal function of body tissues, the excess extracellular matrix produced in liver fibrosis can prevent cells from signalling properly to one another and cause distortion of blood flow through the tissue and scarring.

Immune cells in the liver, known as macrophages, can also contribute to liver fibrosis by secreting signalling proteins, like TGFβ, that continue to promote inflammation and the activation of hepatic stellate cells, driving the progression of liver fibrosis.

Why target liver fibrosis?

Liver fibrosis can be caused by many different liver diseases and dietary factors. Estimates suggest as much as 51.4% of populations have liver fibrosis. While treatments are available for some liver diseases, if liver fibrosis has reached advanced stages through chronic disease, regression is not possible.

The leading cause of liver fibrosis is metabolic dysfunction-associated steatohepatitis (MASH; an advanced stage of MASLD). MASH is the major cause of liver-related mortality, an increasing burden on healthcare systems globally, and is rapidly becoming the leading cause of liver transplantation in the USA. Until this year there were no approved treatments for MASH. In March 2024, the FDA approved Madrigal Pharmaceutical’s Rezdiffra to treat MASH with moderate to advanced liver fibrosis. This is the first drug to show any level of regression of liver fibrosis in MASH.

Oligonucleotide therapies targeted to the liver have successfully used GalNAc as a delivery system. Alnylam Pharmaceuticals has innovated a series of FDA-approved RNAi drugs (givosiran, lumasiran, and vutrisiran) with several other candidates currently undergoing clinical trials.

Though effective in targeting drugs, GalNAc targets hepatocytes, which are not the cell type responsible for liver fibrosis. To be able to effectively target liver fibrosis with the aim of reversing this pathology, we need to target hepatic stellate cells as the cell type responsible for the formation of scar tissue in the liver.

We are actively developing an Optimer delivery vehicle that selectively targets activated hepatic stellate cells, the cells responsible for fibrotic liver disease.

Fluorescence microscopy analysis demonstrates selective targeting of the Optimer® delivery vehicles to the primary hepatic stellate cell population with no targeting to hepatocyte cell populations.

The lead candidate Optimer delivery vehicle does not deliver to other cell types within the liver or other tissues and can deliver functional therapies to HSCs cells, bringing new hope for precision therapies to address liver fibrosis.

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