Infection and Drug Resistance | Volume 15 - Dove Press Open ...

Researchers Describe The Origin And Fate Of Liver Myofibroblasts

Hepatic fibrosis occurs when scar tissue replaces damaged cells in the liver. Over time, accumulating scarring distorts the liver, interferes with its blood supply and may progressively lead to worsening consequences, from cirrhosis to liver failure to liver cancer. In advanced cases, the only treatment is an organ transplant.

In a new paper, published online in the journal Cellular and Molecular Gastroenterology and Hepatology, a team of scientists led by corresponding authors David A. Brenner, M.D., president and CEO of Sanford Burnham Prebys, and Tatiana Kisseleva, M.D., Ph.D., professor of surgery at UC San Diego School of Medicine, describe the origin and fate of liver myofibroblasts -; the cells that form liver scar tissue -; and emerging evidence that liver fibrosis can be reversed if the causative agent is removed.

"Liver fibrosis is quite common, in part because it can be caused by a number of things that damage the organ but result in scarring rather than healthy repair," said Brenner, a gastroenterologist and noted liver disease researcher. "Everything from viral hepatitis to excessive alcohol consumption to non-alcoholic fatty liver disease (NAFLD), which is extremely common in the U.S."

Indeed, it's estimated that NAFLD affects approximately 1 billion people worldwide, or roughly one-quarter of the human population. Roughly 20 percent of patients with NAFLD progress to a more serious form called nonalcoholic steatohepatitis (NASH), characterized by inflammation of the liver, fibrosis and cirrhosis.

In their paper, Brenner, Kisseleva and co-authors explain that myofibroblasts are not present in normal, healthy livers, but activate in response to chronic liver injury, such as excessive alcohol consumption. An inflammatory response triggers activation of hepatic stellate cells (aHSC), which transition from relatively scarce, quiescent, vitamin A-storing cells into proliferative myofibroblasts that secrete the scar forming proteins.

These myofibroblasts begin forming a chicken wire of non-functional scar tissue that, over time, thickens and coalesces to clog and choke the liver, cascading to other, life-threatening conditions.

There are many causes of liver fibrosis and thus, there are no effective therapies currently because most efforts have focused on single targets when the nature of chronic liver injury is incredibly complex."

David A. Brenner, M.D., President and CEO of Sanford Burnham Prebys

An emerging therapeutic approach, said the researchers, is to zero in on disrupting the creation of hepatic myofibroblasts while simultaneously addressing the underlying cause of the liver damage, such as a viral infection or excessive drinking. Do so, the thinking goes, and aHSCs revert to their dormant state and liver fibrosis disappears.

"That means zeroing in on the factors that activate hepatic stellate cells," said Brenner, "the signaling pathways that turn them into scar tissue factories. Recent studies in mouse models and humans have begun to illuminate these cellular and molecular mechanisms. And new single cell technologies and tools like spatial transcriptomics (which can comprehensively characterize tissue organization and architecture at single cell or subcellular resolution) will further the cause."

Additional authors on the study include Hyun Young Kim, Sadatsugu Sakane, Alvaro Eguileor, Raquel Carvalho Gontijo Weber, Wonseok Lee, Xiao Liu, Kevin Lam, Kei Ishizuka, Sara Brin Rosenthal and Karin Diggle, all at UC San Diego.

This study was also recently presented at the Japanese Society of Hepatology, where Brenner gave the state-of-the-science lecture.

Source:

Journal reference:

Kim, H., et al. (2023). The origin and fate of liver myofibroblasts. Cellular and Molecular Gastroenterology and Hepatology. Doi.Org/10.1016/j.Jcmgh.2023.09.008.

Researchers Find How Liver Cells Become Scarring, Worse

La Jolla (California) [US], September 27 (ANI): Hepatic fibrosis happens when the liver's destroyed cells are replaced by scar tissue. Cirrhosis, liver failure, and even liver cancer may develop as a result of the liver's blood flow being disrupted over time by accumulated scarring. An organ transplant is the only option for treatment in severe instances. A group of researchers led by corresponding authors David A. Brenner, M.D., president and CEO of Sanford Burnham Prebys, and Tatiana Kisseleva, M.D., Ph.D., professor of surgery at UC San Diego School of Medicine, describe the origin and fate of liver myofibroblasts, the cells that form liver scar tissue, as well as new research suggesting that liver fibrosis can be reversed if the right conditions are present.

"Liver fibrosis is quite common, in part because it can be caused by a number of things that damage the organ but result in scarring rather than healthy repair," said Brenner, a gastroenterologist and noted liver disease researcher. "Everything from viral hepatitis to excessive alcohol consumption to non-alcoholic fatty liver disease (NAFLD), which is extremely common in the U.S." Indeed, it's estimated that NAFLD affects approximately 1 billion people worldwide, or roughly one-quarter of the human population. Roughly 20 percent of patients with NAFLD progress to a more serious form called nonalcoholic steatohepatitis (NASH), characterized by inflammation of the liver, fibrosis and cirrhosis.

In their paper, Brenner, Kisseleva and co-authors explain that myofibroblasts are not present in normal, healthy livers, but activate in response to chronic liver injury, such as excessive alcohol consumption. An inflammatory response triggers activation of hepatic stellate cells (aHSC), which transition from relatively scarce, quiescent, vitamin A-storing cells into proliferative myofibroblasts that secrete the scar forming proteins. These myofibroblasts begin forming a chicken wire of non-functional scar tissue that, over time, thickens and coalesces to clog and choke the liver, cascading to other, life-threatening conditions.

"There are many causes of liver fibrosis and thus, there are no effective therapies currently because most efforts have focused on single targets when the nature of chronic liver injury is incredibly complex," Brenner said. An emerging therapeutic approach, said the researchers, is to zero in on disrupting the creation of hepatic myofibroblasts while simultaneously addressing the underlying cause of the liver damage, such as a viral infection or excessive drinking. Do so, the thinking goes, and aHSCs revert to their dormant state and liver fibrosis disappears.

"That means zeroing in on the factors that activate hepatic stellate cells," said Brenner, "the signaling pathways that turn them into scar tissue factories. Recent studies in mouse models and humans have begun to illuminate these cellular and molecular mechanisms. And new single cell technologies and tools like spatial transcriptomics (which can comprehensively characterize tissue organization and architecture at single cell or subcellular resolution) will further the cause."  (ANI)

(This story has not been edited by Devdiscourse staff and is auto-generated from a syndicated feed.)

Ascletis Announces Positive Interim Data From The Phase IIb Expansion Cohort Of ASC22 (Envafolimab) For Chronic Hepatitis B Functional Cure

HANGZHOU and SHAOXING, China, Sept. 28, 2023 /PRNewswire/ -- Ascletis Pharma Inc. (HKEX: 1672, "Ascletis") today announces positive interim data from the Phase IIb expansion cohort (the "Expansion Cohort") of subcutaneously administered PD-L1 antibody ASC22 (Envafolimab) for functional cure of chronic hepatitis B (CHB).

The Expansion Cohort is a randomized, single-blind, placebo-controlled and multi-center clinical trial (ClinicalTrials.Gov: NCT04465890) and planned to enroll approximately 50 CHB patients with baseline hepatitis B surface antigen (HBsAg) ≤100 IU/mL who would be treated with 1.0 mg/kg ASC22 or placebo (at a ratio of approximately 4:1) once every two weeks (Q2W) for 24-week treatment plus 24-week follow-up. All patients in both ASC22 and placebo cohorts received nucleot(s)ide analogues (NAs) as a background therapy. In the second quarter of 2023, Ascletis successfully completed the enrollment of 49 CHB patients, including 40 patients in ASC22 cohort and 9 patients in placebo cohort.

Interim analysis was conducted when approximately 50% of the enrolled patients completed 24-week treatment of ASC22 or placebo. The interim analysis included 25 patients who completed 24-week treatment (19 patients in ASC22 cohort and 6 patients in placebo cohort). Topline results indicated that in ASC22 cohort, 4 patients (4/19, 21.1%) achieved HBsAg loss at the end of 24-week treatment. In contrast, there were no patients (0/6, 0%) achieving HBsAg loss at the end of 24-week treatment in the placebo cohort. ASC22 was generally safe and well tolerated. Most of ASC22 drug related adverse effects were Grade 1 or 2.

CHB remains to be a significantly unmet medical need globally, with approximately 86 million people in China and 1.59 million people in the U.S. Infected with hepatitis B virus (HBV)[1].

"While pursuing Phase IIb clinical study of ASC22 (Envafolimab) as monotherapy for CHB patients with baseline HBsAg≤100 IU/mL, we are also engaging global partners to discuss collaboration on combo therapies to achieve higher functional cure rates for HBV." said Dr. Jinzi J. Wu, Founder, Chairman and CEO of Ascletis.

About Ascletis

Ascletis is an innovative R&D driven biotech listed on the Hong Kong Stock Exchange (1672.HK), covering the entire value chain from discovery and development to manufacturing and commercialization. Led by a management team with deep expertise and a proven track record, Ascletis focuses on three therapeutic areas with unmet medical needs from a global perspective: viral diseases, non-alcoholic steatohepatitis (NASH) and oncology. Through excellent execution, Ascletis rapidly advances its drug pipeline with an aim of leading in global competition. To date, Ascletis has multiple drug candidates in its R&D pipeline. The most advanced drug candidates include ASC22 (CHB functional cure), ASC40 (acne), ASC40 (recurrent glioblastoma), ASC40 (NASH), ASC41 (NASH) and ASC61 (advanced solid tumors).

For more information, please visit www.Ascletis.Com.

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SOURCE Ascletis Pharma Inc.

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