Chronic liver diseases represent one of the leading causes of mortality worldwide. According to data from the World Health Organization, liver cirrhosis and other chronic liver diseases alone caused 1.32 million deaths in 2019 (WHO, 2020); more than half of these deaths are due to advanced chronic liver disease (ACLD) and its complications.
The Industrial Doctorate project, entitled “ Development of therapies for hepatic microcirculatory dysfunction and fibrosis in chronic liver disease ”, arises from the need to address the complexity of metabolic dysfunction-associated liver disease (MASLD).
To learn first-hand about the objectives, advances and potential impact of this research, we spoke with Peio Aristu Zabalza . Aristu is the industrial PhD student in the project developed in collaboration between the company Barcelona Liver Bioservices SL (BLB) and the Hepatic Vascular Biology group of the August Pi i Sunyer Institute of Biomedical Research ( IDIBAPS ) of the University of Barcelona. The project has a double aspect; on the one hand, it evaluates a new drug in collaboration with the international pharmaceutical company Gilead Sciences. On the other, it explores a question that has been little studied so far: the study of chronic liver disease in female animal models. “ Most preclinical studies have traditionally been carried out in males, which has left important gaps in how the disease, and treatments, affect females, ” says Aristu.
Chronic liver diseases constitute a major global health challenge, with a considerable impact on patients' quality of life and a high mortality rate. Given this scenario, the search for new therapeutic strategies becomes a priority. As we have indicated before, one of the most important current challenges is the increase in metabolic dysfunction-associated liver disease (MASLD), closely linked to obesity, diabetes and metabolic syndrome , and which affects approximately 25% of the world's population. As Aristu explains, " it is a much more complex type of disease, because there are many factors involved and it is difficult to find a single and effective treatment ."
"Liver disease associated with metabolic dysfunction is a much more complex type of disease, because there are many factors involved and it is difficult to find a single, effective treatment."
New therapeutic strategies
The project research team led by Aristu, accompanied by Jordi Gracia Sancho from the company and Joan Carles García Pagán from the university, has a clear objective: to find new ways to treat serious liver diseases that persist for a long time, what is known as advanced chronic liver disease. They are mainly focused on solving two fundamental problems: on the one hand, poor blood circulation within the smallest vessels of the liver and, on the other, the hardening of the organ due to the accumulation of scar tissue, a process known as fibrosis.
These problems often lead to a serious complication called portal hypertension , which is common in cases of cirrhosis . This condition occurs when pressure increases in a key vein in the liver, called the portal vein. According to Aristu, it is essential to detect it before the portal pressure exceeds a critical threshold, since from that point on , a series of events are triggered that aggravate the progression of the disease.
With this objective, the doctoral student is studying in depth the cells that line the inside of the finest blood vessels in the liver and that are the first to suffer damage . In other words, these cells have small holes or pores, which are essential for the liver to function properly, allowing the passage of nutrients and oxygen from the blood to the liver cells and the elimination of waste.
As the disease progresses, however, these cells deteriorate and stop doing their job properly. As a result, the small blood vessels in the liver lose their characteristics and their ability to facilitate this exchange of substances . This not only worsens blood circulation inside the liver, but also directly contributes to the increase in pressure inside the organ, aggravating portal hypertension. Given that all these cells are connected, “ we believe that understanding and modulating this intercellular communication is key to the development of new therapeutic strategies, starting with intervening on these cells ,” says Aristu.
To address this complex challenge, as previously discussed, the project is deployed in two complementary lines of research. The first focuses on the evaluation of a new experimental drug, a work carried out in collaboration with the international pharmaceutical company Gilead Sciences. The particularity of this compound is that it is designed to act on a recently identified key cellular mechanism, with the aim of restoring the health of the delicate and crucial finest blood vessels in the liver. The results have been very promising: “ a clear reduction in portal pressure has been seen, [..], less inflammation and less fibrosis. All this provides new evidence that may be key to deciding whether to take the step towards a clinical trial, ” concludes Aristu.
In parallel, the second line of research developed by the industrial doctorate delves into a less explored but highly relevant area: differences between the sexes. The research attempts to find out how being male or female can influence the way in which serious liver diseases progress and how organisms respond to different treatments. These studies are mainly carried out in animal models, specifically rats, which develop progressive liver scarring similar to that suffered by humans.
The inclusion of the sex variable is one of the pillars of Aristu's industrial doctorate: " historically, these models have been based mostly on male rats, which has generated a significant bias in research and has led to drugs with different efficacy and safety profiles in men and women ," notes the doctoral student. Biomedical research has begun to recognize the importance of balancing sex in preclinical studies to avoid these biases.
"Historically, these [preclinical] models have been based mostly on male rats, which has generated significant bias in research and led to drugs with different efficacy and safety profiles in men and women."
Promising preliminary results and socio-economic impact, towards personalized medicine
The results obtained so far are encouraging. In the project developed with Gilead Sciences, it has shown “ a clear reduction in portal pressure, an improvement in the state of the hepatic endothelium, less inflammation and less fibrosis ,” says Arsitu. This new preclinical evidence is crucial and could support the design of future clinical trials.
Regarding the second project, the study of sex differences in rat models with alcohol-induced and secondary biliary cirrhosis has revealed “ significant differences in disease progression according to sex .” At the molecular level, it has been identified that “ sex hormones play a key role in the regulation of hepatic signaling pathways ,” explains Aristu.
Both projects are currently in their final stages. The scientific article related to the collaboration with Gilead Sciences is being written, and the article on sex differences in liver disease has already been submitted to high-impact scientific journals for publication.
The potential impact of this Industrial Doctorate is significant. On the one hand, the validation of new therapeutic targets and the development of more effective drugs could substantially improve the treatment of advanced chronic liver disease and, in the long term, reduce the need for liver transplants . Although the team is cautious, “ there is still a long way to go before this drug can become a first-line therapy ”, the results are a step forward.
Furthermore, research on sex differences in liver disease directly contributes to progress towards more personalized and precision medicine. Understanding how sex and, in future research, age modulate disease and response to treatments is essential for designing more effective and equitable therapies.
The collaboration between the academic environment (IDIBAPS-UB) and the business environment (Barcelona Liver Bioservices SL) is a key element of success, of this project and of many other success stories . Barcelona Liver Bioservices brings great experience in advanced techniques, such as hemodynamic liver surgeries in animal models. This synergy “ not only improves the quality of preclinical studies, but also promotes technology transfer, bringing scientific advances closer to their application in the treatment of liver disease ”, highlights Aristu. In addition, the connection with the global pharmaceutical industry, such as Gilead Sciences, allows preclinical models to be validated in an applied environment and opens doors to strategic collaborations, including the transfer of clinical data for retrospective analyses.
The synergy between the company and the university "not only improves the quality of preclinical studies, but also promotes technology transfer, bringing scientific advances closer to their application in the treatment of liver disease."
