Tecnologies per llicenciar

New HRI activators for the treatment of non-alcoholic steatohepatitis (NASH)

Advantages

Several companies are developing FGF21 analogs that mimic the beneficial effects of this hormone. These long-acting FGF21 analogs are proteins that require subcutaneous administration and that are more potent than native FGF21. This increase in the potency of the analogs can exacerbate some of the non-wanted effects of FGF21, such as the reported increase in bone loss caused by this hormone.

The HRI activators might avoid the side effects observed with FGF21 analogs due to the presence of a negative feedback mechanism activated by endogenous FGF21.

Goal

We search for partners or investors to further develop the compounds, through a co-development and license agreement, or a company creation.

Intellectual Property

PCT/EP2017/057398

Reference

UBTT0297

Contact

Inma Íñiguez
Email: iiniguez@fbg.ub.edu
Tel: +34 934 039 798

Executive summary

A research group, with wide experience in the study of the mechanism involved in the development of insulin resistance and type 2 diabetes mellitus as well as in non-alcoholic fatty liver disease, has generated a new family of compounds for the treatment of non-alcoholic steatohepatitis (NASH), together with experts in chemical synthesis and pharmacological evaluation.

The interdisciplinary group is looking for a license, but other collaborations may be considered.

Introduction

Non-alcoholic steatohepatitis (NASH) is a chronic condition characterized by an abnormal accumulation of lipids within liver cells, as well as inflammation, hepatocyte damage and fibrosis in some cases.

Fibroblast growth factor 21 (FGF21) is a hormone mainly produced by the liver with effects that alleviate insulin resistance and NASH. The research group has reported that activation of heme-regulated eIF2α kinase (HRI) increases hepatic and plasma levels of FGF21, indicating that this kinase is a pharmacological target for regulating FGF21 levels (Diabetes 2016;65:3185-99).

Description

The research group has generated a new family of small chemical compounds that act as HRI activators.

It has been observed that following oral administration the lead compound activates HRI and increases hepatic and plasma levels of FGF21.

They have observed that mice fed with a high-fat diet for 10 weeks treated by oral gavage with an HRI activator for the last two weeks, had an improvement in glucose intolerance. In addition, our HRI activator caused a spectacular reduction in liver triglyceride accumulation, suggesting that these compounds might be potential candidates for the treatment of NASH.

The effects of the HRI activator were dependent on FGF21 because they were abolished in FGF21-null mice.

Current stage of development

The following valorization plan has been defined for 2019:

  1. Synthesis of new compounds with better profile to select the best for a proof of concept in an animal model of NASH.
  2. Selection of an optimized lead through assessment of in vitro studies of Cytotoxicity and basic Drug Metabolism and Pharmacokinetics (DMPK).
  3. Demonstration of the efficacy of HRI activator in NASH animal models:
  • The high-fat, cholesterol, and fructose diet.
  • The methionine/choline-deficient diet.
  • Model consisting in the administration of CCl4 to mice fed a Western diet.

 

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Tags: Life Sciences, Salut i ciències de la vida

 

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