Nano-Technology Enabled Repositioning of Cannabinoids for Treating NAFLD

Description du projet

Un système d’administration des médicaments à base de nanoparticules pour traiter la stéatose hépatique

La stéatose hépatique non alcoolique (NAFLD pour «non-alcoholic fatty liver disease») est due à l’accumulation de graisse dans le foie chez les personnes généralement en surpoids. Les récepteurs cannabinoïdes-1 (CB1R) présents dans le foie peuvent augmenter la production hépatique de glucose, la résistance à l’insuline et la lipogenèse de novo, et diminuer l’oxydation des acides gras. Toutefois, les bloqueurs de CB1R ne sont plus utilisés chez l’homme en raison de leurs effets secondaires neuropsychiatriques. Le projet NANOFLD, financé par l’UE, entend réintroduire les bloqueurs de CB1R dans les essais cliniques en utilisant un système d’administration de médicaments nanométrique innovant qui cible précisément les CB1R hépatiques. Après avoir réussi à encapsuler le bloqueur de CB1R de nouvelle catégorie dans des nanoparticules et testé leur stabilité, leur efficacité et leur puissance, l’équipe étudiera la biodistribution des bloqueurs de CB1R dans les nanoparticules ainsi que la manière dont ce système d’administration de médicaments nanométrique affecte les cellules hépatiques.

Objectif

Obesity is a catalyst for numerous conditions; the most notable is non-alcoholic fatty liver disease (NAFLD), for which currently no drug therapy has been approved by the FDA and EMA for its treatment. The endocannabinoid (eCB) system triggers the development of obesity and its related comorbidities, specifically NAFLD. eCBs, via activating the cannabinoid-1 receptors (CB1Rs) in the liver, increase hepatic glucose production, insulin resistance, and de novo lipogenesis, and decrease fatty acid oxidation. Accordingly, globally-acting CB1R blockers improve these parameters both in rodents and humans. However, owing to their neuropsychiatric side effects, they were withdrawn from the market and are no longer available for clinical use. NANOFLD aims to revive their clinical development and testing by utilizing an innovative nanometric drug delivery system for the hepatic targeting of globally-acting CB1R blockers for treating NAFLD. In the framework of my ERC-StG grant, CaNanoBinoids, my team successfully encapsulated the first-in-class CB1R blocker, rimonabant, in nanoparticles (NPs), tested their stability, efficacy, and potency, and demonstrated their therapeutic potential in ameliorating NAFLD, insulin resistance, and dyslipidemia in mice. To further translate our findings into clinical practice, the present PoC application builds on and expands this avenue of research by achieving several necessary steps including biodistribution, hepatic cellular fate, and PK studies of our novel nanometric drug delivery system. Importantly, we have secured the IP, conducted a specific market assessment, targeted regulatory constraints, implemented a business development plan, consulted with professionals in the field, and developed contacts with industry. When this project is completed, we expect to have introduced a unique innovation to treat NAFLD and its metabolic abnormalities, further promoting the idea to clinically test CB1R blockers encapsulated in NPs against NAFLD.