Cannabinoid-1 receptorn som terapi för fettleversjukdom
- Diarienummer
- SIP21-0048
- Projektledare
- Björkström, Niklas
- Start- och slutdatum
- 221101-281031
- Beviljat belopp
- 3 124 436 kr
- Förvaltande organisation
- Karolinska Institutet
- Forskningsområde
- Livsvetenskaperna
Summary
Nonalcoholic Fatty Liver Disease (NAFLD) is projected to become the leading cause of liver-related malignancy and mortality within 20 years. However, no treatments are currently available. Endocannabinoids, via activation of the cannabinoid-1 receptors (CB1Rs) in the liver, contribute to the development of NAFLD. While chronic CB1R blockers have shown encouraging results in improving hepatic metabolism and preventing NAFLD both in rodents and humans, they are no longer available for clinical use because of their neuropsychiatric side effects. Therefore, developing a pharmacological approach to inhibit CB1Rs exclusively in the periphery without affecting the central nervous system holds great promises for the treatment of NAFLD. We have demonstrate that novel drugs, develop by the applicants, can target the CB1Rs only in peripheral organs, including the liver. These CB1R antagonists efficiently reversed NAFLD, without centrally-mediated side effects. Here, we propose to validate the therapeutic potential of peripherally restricted CB1R antagonists for the treatment of NAFLD. We will delineate the biodistribution, mechanism of actions, and translatability of peripherally restricted CB1R blockade to reverse NAFLD. By synergizing our individual expertise, we expect to provide the rationale for further development and clinical testing of peripherally restricted CB1R antagonists for the treatment of NAFLD.
Populärvetenskaplig beskrivning
Non-alcoholic fatty liver disease (NAFLD) is a chronic disease in which patients accumulate fat in their liver. While this phenomenon usually occurs in alcoholism, it is also often observed in obese individuals who do not consume excessive amounts of alcohol. Fat accumulation in the liver can damage cells and lead to severe scaring and cancer. While NAFLD is a very common disease, there are currently no approved drugs to treat it. Although it represents an unmet medical need and an attractive market, most clinical trials have failed due to a lack of understanding of the pathogenesis at the molecular level and its conservation in humans. Endocannabinoids are lipid molecules that act on a cellular receptor, called CB1. Activation of CB1 receptors increases the synthesis of fat in the liver, whereas its inhibition by CB1 blockers increases the elimination of fat from the liver, suggesting that these drugs have the potential to treat fatty liver disease. We have generated a strong evidence showing that new CB1 inhibitors can improve liver health in an animal model of NAFLD. By designing compounds that do not penetrate the brain, we avoided the psychiatric effects of such drugs, but restricted their effects to the periphery. Our two research groups will combine their strong expertise in drug development and delivery, and human pre-clinical models of NAFLD to validate the therapeutic potential of peripherally restricted CB1 blockers to combat NAFLD. To this end, we will study the mechanism of action of these inhibitors as well as their translatability to humans. By synergizing our competences, we expect to build a solid foundation for the development of novel drugs for the treatment of NALFD.