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Fatty liver Nano-/Antibody Therapy - (FAITH)

Project description

A novel antibody therapy against non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease is strongly associated with poor nutrition and obesity, often leading to non-alcoholic steatohepatitis (NASH), fibrosis and liver cancer. Anti-platelet therapy has emerged as a potential strategy against NASH but exhibits adverse health effects. Researchers of the EU-funded FAITH project have previously shown that blocking the platelet-derived surface molecule GPIba prevents NASH and liver cancer in experimental models without any side effects. With this project, they plan to generate antibodies to block the binding of thrombin to GPIba without interfering with its role in platelet-derived aggregation and haemostasis.

Objective

Changes in life-style and nutrition have increased the incidence of obesity/overweight and metabolic syndrome resulting in a pathology called Non-alcoholic fatty liver disease (NAFLD). Currently, 130 million people in Western countries have NAFLD and this number is constantly increasing. A significant number of patients develop non-alcoholic steatohepatitis (NASH), fibrosis and subsequently liver cancer. At the same time no efficient therapeutics exist to treat NASH or NASH-liver cancer transition.
We could demonstrate that infiltration and aggregation of platelets in the liver is the initial and the disease accompanying/maintaining process.

Application of a conventional antiplatelet-therapy (APT) prevented or reverted established NASH in mice and men and abandoned subsequent liver cancer development in mouse models.

Existing APT bear unwanted side effects and health issues. We identified the platelet-derived surface molecule GPIba as the critical mediator of platelet-derived immune activation, NASH and liver cancer. Using an antibody blocking the thrombin-binding site of GPIba, prevented established NASH, fibrosis and liver cancer without affecting hemostasis (Malehmir et al. 2019 Nature Medicine). The identified novel strategy differentiates itself from all other approaches to treat NASH due to some unique application opportunities:
(I) no necessity to change patients’ nutritional habits, resulting in a high acceptance on the patient´s side,
(II) no systemic immunosuppression of the patients´ immune system and
(III) circumventing unwanted severe side effects of conventional APT by decoupling platelet-derived inflammatory function from platelet-derived aggregation/hemostasis.

We intend (1) to produce nanobodies/antibodies that functionally block the human thrombin binding site of GPIba, (2) to confirm the therapeutic activity in preclinical NASH models carrying a humanized GPIba and (3) to lay the ground for necessary subsequent steps towards the market.

Host institution

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Net EU contribution
€ 150 000,00
Address
IM NEUENHEIMER FELD 280
69120 Heidelberg
Germany

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Region
Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis
Activity type
Research Organisations
Links
Total cost
No data

Beneficiaries (1)