Descripción del proyecto
Una nueva terapia de anticuerpos contra la esteatosis hepática no alcohólica
La esteatosis hepática no alcohólica está estrechamente asociada con una mala nutrición y obesidad, y a menudo da lugar a esteatohepatitis no alcohólica (EHNA), fibrosis y cáncer hepático. El tratamiento antiplaquetario ha surgido como una posible estrategia frente a la EHNA, si bien presenta efectos adversos para la salud. Los investigadores del proyecto financiado con fondos europeos FAITH habían demostrado previamente que el bloqueo de la molécula de superficie derivada de plaquetas GPIba previene la EHNA y el cáncer hepático en modelos experimentales, sin ningún efecto secundario. En este proyecto, planean generar anticuerpos para bloquear la unión de la trombina a GPIba sin interferir con su función en la hemostasia y la agregación derivada de plaquetas.
Objetivo
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.
Ámbito científico
CORDIS clasifica los proyectos con EuroSciVoc, una taxonomía plurilingüe de ámbitos científicos, mediante un proceso semiautomático basado en técnicas de procesamiento del lenguaje natural.
CORDIS clasifica los proyectos con EuroSciVoc, una taxonomía plurilingüe de ámbitos científicos, mediante un proceso semiautomático basado en técnicas de procesamiento del lenguaje natural.
Programa(s)
Régimen de financiación
ERC-POC - Proof of Concept GrantInstitución de acogida
69120 Heidelberg
Alemania