Hépatinov - Priority clinical challenges

Because of its strong association with liver-related morbidity and premature death, fibrosis has become the principal focus in secondary care. This is particularly true in patients with non-alcoholic fatty liver disease (NAFLD) which accounts for approximately 25% of all liver diseases.

In the case of primary liver tumours (PLT), some molecular targets for precision medicine have been identified. In particular, immune checkpoint inhibitor-based treatments have shown promising results. To refine treatment selection and promote the combination of systemic and loco-regional therapeutic approaches (such as new types of tumour embolization, direct injections into the tumour and innovative radiotherapy), new immune prognostic signatures of efficacy and toxicity need to be defined.
In the context of end-stage liver disease, bacterial infection is one of the most important causes of acute decompensation and death. It is of crucial importance to obtain a better knowledge of bacterial resistance in severely ill patients.
Despite the considerable efforts that have been devoted to the development of orphan drugs, many genetic and rare liver diseases (GARLDs) still lack effective cures and call for new therapies. Since a majority of GARLDs stem from genetic disorders, recent progress in tailor-made pharmacological and gene therapies could offer more options to treat them.

The goals

Objective 1 Objective 2 Objective 3 Objective 4 Objective 5 Objective 6 Objective 7

Pathological processes in the extracellular compartment and endothelium of patients with liver diseases.
Hépatinov intends to:

identify at an early stage of NALFD the set of proteins from the hepatic extracellular compartment that are sensitive to oxidative modifications;

Chronic liver injury is characterised by the deposition of extracellular matrix in response to persistent liver damage. Although oxidative stress is recognised as the second hit which leads from steatosis to NASH and fibrosis reactive oxygen species within the extracellular compartment have been little described and their importance for disease progression is totally unexplored. As all proteins are not equally sensitive to oxidation, Hépatinov will identify which proteins are oxidised at various levels of stress and analyse their ability to induce disease progression.

identify the in vitro and in vivo toxic effects on endothelial cells in patients with NAFLD;

Vascular endothelial dysfunction seems to be an early event in NAFLD and may be implicated in both liver injury progression and systemic atherosclerosis. This hypothesis will be studied by assessing the association between pre - and postprandial circulating lipid profiles and vascular endothelial dysfunction in a population of NAFLD patients.

assess the quality of collagen fibres inliver fibrosis during the different stages of chronic liver disorders;

Second-harmonic generation and synchrotron deep-ultraviolet microscopies allow for the qualitative evaluation of fibrosis by identifying individual collagen fibrils and quantifying their physical properties. Diagnosis and prognosis will be established by assessing the quality of collagen fibres in a cohort of patients displaying different degrees of fibrosis (F0-F4) in the context of different aetiologies (NAFLD, alcoholic liver disease and liver disease after the cure of HCV).

Identification of signatures for the development of a rationale and risk evaluation of immunotherapy in patients with primary liver tumours (PLT).

The development of drugs for PLT has been characterised by numerous failures and a comprehensive biomarker analysis has not yet been reported notably in the case of cholangio carcinoma (CC). Hépatinov will improve the efficacy and safety of immunotherapy

by identifying new genomic/phenotypic tumour signatures,
by identifying the specific signatures of autoimmune serum and their dynamic changes during immunotherapy,
by identifying global serum immune response signatures against gut microbiota and their changes under immunotherapy (using imaging-based prognostic techniques, including combinations of morphological and functional imaging strategies - immunoTEP, tumour elastometry and vascular dynamic imaging) and
by propose new methods of manipulating the gut microbiome in order to extend immune checkpoint therapy to patients with a primary or a secondary resistance.

For data integration, Hépatinov will rely on regularised and sparse generalised canonical correlation analysis (RGCCA) which is a general framework for the joint analysis of multiple sources.

Innovative loco-regional and combined immunotherapy-based approaches for primary liver tumours.

Technological advances have improved the safety and effectiveness of tumour embolization and radiation therapy in the management of primary tumours. Combining these therapies could improve the survival of patients with CC. Although numerous studies have demonstrated that the presence of circulating tumour cells (CTCs) is significantly associated with the prognosis for primary liver tumours, new approaches such as the identification of tumour cell surface antigen and cancer-associated macrophage-like (CAML) cells are needed, particularly in the context of the innovative therapies described above.

Hépatinov will aim at

the evaluation of new agents for intravascular embolization;

i.e. radioembolization with HO-166, resorbable drug-loaded embolics, intra-tumour delivery of checkpoint inhibitors using intra-arterial, intra-hepatic or direct percutaneous administration, and the direct injection into the tumour of oncolytic viruses JX594-Transgene.

The evaluation of the immunomodulatory effects of chemo- and radio-embolization using these new agents and/or combined immune-based therapies;
study of 3D conformal radiotherapy and intensity-modulated radiotherapy (IMRT) in patients with CC;
study of factors influencing early recurrence.

Study of the in vivo evolution of bacterial resistance in patients with end-stage liver disorders.

Hépatinov will perform a comprehensive analysis of bacterial adaptations to the antibiotic protocols used to treat infected cirrhotic patients and ultimately to propose possible alternate therapies to bypass this bacterial resistance to antibiotics.

Development of tailor-made pharmacological therapies in genetic cholestasis.

Progressive familial intrahepatic cholestasis type 2 (PFIC2) and type 3 (PFIC3) are autosomal recessive types of hepatocellular cholestaseswhich manifest themselves usually during the first year of life and require liver transplantation in childhood.The need for alternative therapies is of crucial importance. Bile acid synthesis defects (BASD) are also severe childhood and genetic cholestasis disorders that benefit from cholic acid therapy. Data concerning the outcomes in adulthood of patients treated with cholic acid are deficient.

Development of gene therapy trials for genetic liver diseases.

Validation in pre-clinical models is required before gene therapy can be translated to humans. Hépatinov focuses on the following diseases:

glycogen storage diseases (GSD) using AAV vectors;
Crigler Najjar disease;
PFIC2 and PFIC3 using liver tropic AAV vectors.

Development of cell therapy for liver diseases.

The UCLouvain pediatric hepatology and cell therapy laboratory has a long history of hepatocyte and stem cell transplantation in inborn and acquired liver diseases. Discovery and in-depth investigations of anti-inflammatory and anti-fibrotic properties of a specific liver derived progenitor cell have led to develop their clinical use in fibro-inflammatory liver diseases.

Priority clinical challenges

Because of its strong association with liver-related morbidity and premature death, fibrosis has become the principal focus in secondary care. This is particularly true in patients with non-alcoholic fatty liver disease (NAFLD) which accounts for approximately 25% of all liver diseases.

Pathological processes in the extracellular compartment and endothelium of patients with liver diseases. Hépatinov intends to:

Identification of signatures for the development of a rationale and risk evaluation of immunotherapy in patients with primary liver tumours (PLT).

Innovative loco-regional and combined immunotherapy-based approaches for primary liver tumours.

Study of the in vivo evolution of bacterial resistance in patients with end-stage liver disorders.

Development of tailor-made pharmacological therapies in genetic cholestasis.

Development of gene therapy trials for genetic liver diseases.

Development of cell therapy for liver diseases.

2024 Publications

2023 Publications

2022 Publications

2021 Publications

2020 Publications

Hépatinov develops innovative therapeutic and diagnostic approaches for hepatic pathologies

Pathological processes in the extracellular compartment and endothelium of patients with liver diseases.
Hépatinov intends to:

Hépatinov develops innovative therapeutic
and diagnostic approaches for hepatic pathologies