Science sub-journal: A new target for advanced nonalcoholic fatty liver disease

Using the latest techniques — including monocytes sequencing of mouse and human liver tissue and advanced mouse 3D glass imaging to characterize critical scarring liver cells — researchers have discovered new drug candidate targets for the treatment of nonalcoholic fatty liver disease (NAFLD
).
The study was led by researchers at the Icahn School of Medicine at Mount Sinai
.

Using these innovative methods, the researchers discovered a cell-to-cell communication network that drives scarring
as liver disease progresses.
The findings, published Jan.
4 in the journal Science Translational Medicine, could lead to new treatments
.
The study was led by researchers at the Icahn School of Medicine at Mount Sinai
.

NAFLD, characterized by liver fat, is often associated with type 2 diabetes, high blood pressure, and elevated blood lipids, and is a worldwide threat
.
In the United States, an estimated 30 to 40 percent of adults are affected, and about 20 percent of these patients have more advanced nonalcoholic steatohepatitis (NASH), which is characterized by inflammation of the liver and may progress to advanced scarring (cirrhosis) and liver failure
.

NASH is also the fastest-growing cause of
liver cancer worldwide.
Trying to stop fibrosis is central to treating NASH because late NASH is caused by the accumulation of fibrosis or scarring, the researchers said, but there are currently no approved drugs
for this purpose.

As part of the experiment, the researchers performed mononuclear sequencing
on mouse models with NASH and human liver tissue from 9 NASH patients and 2 control groups in parallel studies.
They found 68 pairs of common potential drug targets in both species
.
In addition, the researchers investigated one of the existing anti-cancer drugs by testing them in mice as a proof of concept
.

"Our aim is to understand the basis of this fibrotic scar and, by studying hepatic stellate cells (key scar-producing cells in the liver), identify drug targets that may lead to new treatments for advanced NASH," said
senior study author Scott L.
Friedman, PhD.
"Combined with this new glass liver imaging method—an advanced tissue clearance method that provides deep insight—and gene expression analysis of individual stellate cells, we have a whole new understanding of
how these cells develop scarring as NASH progresses to an advanced stage.
"

The researchers found that in advanced disease, a dense network of interactions is formed between stellate cells, facilitating these 68 unique interaction pairs
that were not previously found in the disease.

"We confirmed the importance of such a pair of proteins, NTF3-NTRK3, using a molecule that has already been developed to block NTRK3 in human cancers and re-using it to build its potential as a new drug against NASH fibrosis," said
first author Shuang (Sammi) Wang, PhD, an instructor in the Division of Liver Diseases.
"This new understanding of fibrosis development suggests that late fibrosis may have a unique signal to accelerate scarring, which represents a previously unrecognized set of drug targets
.
"

The researchers hypothesized that as the disease progressed, the pathways through which cells communicate with each other also evolved, so some drugs may be more effective in the early stages and others may be more effective
at a later stage.
The same drug may not work
at all stages of the disease.

The researchers are currently working with chemists at Mount Icahnai to further optimize NTRK3 inhibitors
for the treatment of liver fibrosis.
Next, the researchers plan to functionally screen all candidate interactors in the cell culture system and then test them in preclinical models of liver disease, just as they did with NTRK3
.
In addition, they hope to expand their efforts to determine whether similar interactions between fibrous cells constitute fibrosis
in other tissues, including the heart, lungs, and kidneys.