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A Korean research team develops a new clinical candidate for fatty liver disease
A team of Korean researchers have succeeded in developing a new drug candidate for the treatment of non-alcoholic fatty liver disease (NAFLD) acting on peripheral tissues. To date, there has not been an optimal treatment for non-alcoholic steatohepatitis (NASH), and this discovery is expected to set the grounds for the development of new drugs that can safely suppress both liver fat accumulation and liver fibrosis at the same time. A joint research team led by Professor Jin Hee Ahn from Gwangju Institute of Science and Technology (GIST) and Professor Hail Kim from the KAIST Graduate School of Medical Science and Engineering developed a new chemical that can suppress disease-specific protein (HTR2A) through years of basic research. The team also revealed to have verified its efficacy and safety through preclinical tests (animal tests) at JD Bioscience Inc., a start-up company founded by Professor Ahn. Although NAFLD has a prevalence rate as high as 20-30%, and about 5% of the global adult population suffers from NASH, there are no commercial drugs targeting them to date. NAFLD is a chronic disease that starts from the fatty liver and progresses into steatohepatitis, fibrosis, cirrhosis, and liver cancer. The mortality rate of patients increases with accompanied cardiovascular diseases and liver-related complications, and appropriate treatment in the early stage is hence necessary. < Figure 1. Strategy and history of 5HT2A antagonists. Library and rational design for the development of compound 11c as a potent 5HT2A antagonist. Previous research efforts were discontinued due to limited oral absorption and safety. A therapeutic candidate to overcome this problem was identified and phase 1 clinical trials are currently in progress. > The new synthetic chemical developed by the joint GIST-KAIST research is an innovative drug candidate that shows therapeutic effects on NASH based on a dual action mechanism that inhibits the accumulation of fat in the liver and liver fibrosis by suppressing the serotonin receptor protein 5HT2A. The research team confirmed its therapeutic effects in animal models for NAFLD and NASH, in which hepatic steatosis and liver fibrosis* caused by fat accumulation in the liver were suppressed simultaneously by 50-70%. *fibrosis: stiffening of parts of the liver, also used as a major indicator to track the prognosis of steatosis The research team explained that the material was designed with optimal polarity and lipid affinity to minimize its permeability across the blood-brain barrier. It therefore does not affect the brain, and causes little side effects in the central nervous system (CNS) such as depression and suicidal ideations, while demonstrating excellent inhibition on its target protein present in tissues outside brain (IC50* = 14 nM). The team also demonstrated its superior efficacy in improving liver fibrosis when compared to similar drugs in the phase 3 clinical trial. *IC50 (half maximal inhibitory concentration): the concentration at which a chemical suppresses 50% of a particular biological function < Figure 2. GM-60106 (11c)'s effect on obesity: When GM-60106 was administered to an obese animal model (mice) for 2 months, body weight, body fat mass, and blood sugar were significantly reduced (a-d). In addition, the steatohepatitis level (NAFLD Activity Score) and the expression of genes of the treated mice involved in adipogenesis along with blood/liver fat decreased (e-h) > Based on the pharmacological data obtained through preclinical trials, the team evaluated the effects of the drug on 88 healthy adults as part of their phase 1 clinical trial, where the side effects and the safe dosage of a drug are tested against healthy adults. Results showed no serious side effects and a good level of drug safety. In addition, a preliminary efficacy evaluation on eight adults with steatohepatitis is currently underway. Professor Jin Hee Ahn said, “The aim of this research is to develop a treatment for NASH with little side effects and guaranteed safety by developing a new target. The developed chemical is currently going through phase 1 of the global clinical trial in Australia through JD Bioscience Inc., a bio venture company for innovative drug development.” he added, “The candidate material the research team is currently developing shows not only a high level of safety and preventative effects by suppressing fat accumulation in the liver, but also a direct therapeutic effect on liver fibrosis. This is a strength that distinguishes our material from other competing drugs.” < Figure 3. Efficacy of GM-60106 (11c) on liver fibrosis: When GM-60106 was administered to a steatohepatitis model (mice) for 3 months, the expression of genes associated with tissue fibrosis was significantly reduced (b-c). As a result of a detailed analysis of the tissues of the animal model, it was confirmed that the rate of tissue fibrosis was reduced and the expression rate of genes related to tissue fibrosis and inflammation was also significantly reduced (e-h). > Professor Hail Kim from KAIST said, “Until now, this disease did not have a method of treatment other than weight control, and there has been no attempt to develop a drug that can be used for non-obese patients.” He added, “Through this research, we look forward to the development of various treatment techniques targeting a range of metabolic diseases including NASH that do not affect the weight of the patient.” This study, conducted together by the research teams led by Professor Ahn from GIST and Professor Kim from KAIST, as well as the research team from JD Bioscience Inc., was supported by the Ministry of Science and ICT, and the National New Drug Development Project. The results of this research were published by Nature Communications on January 20. The team also presented the results of their clinical study on the candidate material coded GM-60106 targeting metabolic abnormality-related MASH* at NASH-TAG Conference 2024, which was held in Utah for three days starting on January 4, which was selected as an excellent abstract. *MASH (Metabolic Dysfunction-Associated Steatohepatitis): new replacement term for NASH
Microscopy Approach Poised to Offer New Insights into Liver Diseases
Researchers have developed a new way to visualize the progression of nonalcoholic fatty liver disease (NAFLD) in mouse models of the disease. The new microscopy method provides a high-resolution 3D view that could lead to important new insights into NAFLD, a condition in which too much fat is stored in the liver. “It is estimated that a quarter of the adult global population has NAFLD, yet an effective treatment strategy has not been found,” said professor Pilhan Kim from the Graduate School of Medical Science and Engineering at KAIST. “NAFLD is associated with obesity and type 2 diabetes and can sometimes progress to liver failure in serious case.” In the Optical Society (OSA) journal Biomedical Optics Express, Professor Kim and colleagues reported their new imaging technique and showed that it can be used to observe how tiny droplets of fat, or lipids, accumulate in the liver cells of living mice over time. “It has been challenging to find a treatment strategy for NAFLD because most studies examine excised liver tissue that represents just one timepoint in disease progression,” said Professor Kim. “Our technique can capture details of lipid accumulation over time, providing a highly useful research tool for identifying the multiple parameters that likely contribute to the disease and could be targeted with treatment.” Capturing the dynamics of NAFLD in living mouse models of the disease requires the ability to observe quickly changing interactions of biological components in intact tissue in real-time. To accomplish this, the researchers developed a custom intravital confocal and two-photon microscopy system that acquires images of multiple fluorescent labels at video-rate with cellular resolution. “With video-rate imaging capability, the continuous movement of liver tissue in live mice due to breathing and heart beating could be tracked in real time and precisely compensated,” said Professor Kim. “This provided motion-artifact free high-resolution images of cellular and sub-cellular sized individual lipid droplets.” The key to fast imaging was a polygonal mirror that rotated at more than 240 miles per hour to provide extremely fast laser scanning. The researchers also incorporated four different lasers and four high-sensitivity optical detectors into the setup so that they could acquire multi-color images to capture different color fluorescent probes used to label the lipid droplets and microvasculature in the livers of live mice. “Our approach can capture real-time changes in cell behavior and morphology, vascular structure and function, and the spatiotemporal localization of biological components while directly visualizing of lipid droplet development in NAFLD progression,” said Professor Kim. “It also allows the analysis of the highly complex behaviors of various immune cells as NAFLD progresses.” The researchers demonstrated their approach by using it to observe the development and spatial distribution of lipid droplets in individual mice with NAFLD induced by a methionine and choline-deficient diet. Next, they plan to use it to study how the liver microenvironment changes during NAFLD progression by imaging the same mouse over time. They also want to use their microscope technique to visualize various immune cells and lipid droplets to better understand the complex liver microenvironment in NAFLD progression.
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