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Methods and pharmaceutical compositions for modulating autophagy

a technology of autophagy and composition, which is applied in the direction of antibody medical ingredients, peptides/protein ingredients, peptides, etc., can solve the problem that the role of dbi secretion in the feedback regulation of autophagy has never been investigated

Pending Publication Date: 2020-08-27
INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM) +3
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about methods and medicine to control autophagy. This is how cells dispose of unnecessary materials. The invention is described in the claims.

Problems solved by technology

However, the role of DBI secretion in the feedback regulation of autophagy has never been investigated.

Method used

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  • Methods and pharmaceutical compositions for modulating autophagy
  • Methods and pharmaceutical compositions for modulating autophagy
  • Methods and pharmaceutical compositions for modulating autophagy

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[0106]Materials and Methods

[0107]Chemicals, cell lines and culture conditions. Unless otherwise indicated, media and supplements for cell culture were purchased from Gibco-Invitrogen (Carlsbad, Calif., USA), plastic ware from Corning B.V. Life Sciences (Schiphol-Rijk, The Netherlands), and chemicals from Sigma-Aldrich (St Louis, Mo., USA). All cell lines were cultured at 37° C. under 5% CO2, in a medium containing 10% fetal bovine serum, 100 mg / L sodium pyruvate, 10 mM HEPES buffer, 100 units / mL penicillin G sodium and 100 μg / mL streptomycin sulfate. In addition, cell type-specific culture conditions include Dulbecco's modified Eagle's medium (DMEM) for human cervical carcinoma HeLa cells and human brain neuroglioma H4 cells as well as their GFP-LC3-expressing derivatives. Minimum Essential Medium Eagle (EMEM) supplemented as above plus 2mM Glutamine and 1% non-essential amino acids (NEAA) for human hepatocyte carcinoma Hep G2 cells. Cells were seeded in 6-, 94-well plates and grown...

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Abstract

Autophagy is typically activated by starvation, allowing cells and organisms to mobilize their energy reserves. It is known that pharmacological modulation of autophagy represents a therapeutic potential. Here the inventors report that a protein that is released from cells in an unconventional, autophagy-dependent manner, namely, diazepam binding inhibitor (DBI), regulates autophagy. In particular, the inventors demonstrate that DBI inhibits autophagy and that the supply of recombinant DBI to mice enhanced glycolysis, enhanced lipogenesis, and inhibited fatty acid oxidation. The inventors show that neutralisation of DBI by a monoclonal antibody and an active immunization by means of an immunogenic DBI derivative eliciting autoantibodies induce autophagy and lead to metabolic changes that increase starvation-induced weight loss, reduce food intake upon refeeding, and reduce weight gain in response to hypercaloric diets. Accordingly, the present invention relates to methods and pharmaceutical compositions for modulating autophagy based on the modulation of the activity or expression of DBI.

Description

FIELD OF THE INVENTION[0001]The present invention relates to methods and pharmaceutical compositions for modulating autophagy.BACKGROUND OF THE INVENTION[0002]Autophagy (“self-eating”) constitutes one of the most spectacular, though subtly regulated phenomena in cell biology and plays a key role in the maintenance of cellular and organismal homeostasis by facilitating the turnover of cytoplasmic structures and allowing cells to adapt to changing and stressful conditions including nutrient deprivation (1, 2). The cellular secretion of several leaderless proteins (which can only be released through an unconventional pathway bypassing Golgi) is strongly associated with autophagy (3-7). One such protein is a phylogenetically ancient factor known as diazepam binding protein (DBI) or acyl coenzyme A (CoA)-binding protein (ACBP) (3, 4). Human or mouse DBI is a small protein of 87 amino acids (10 kDa) that has two totally distinct functions, namely as ACBP within cells (where it binds to lo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17C07K16/18A61K39/00A61K39/39G01N33/68
CPCC07K2317/24C07K16/18C07K2317/21G01N33/68A61K39/0005A61K39/39A61K38/17A61P3/04A61K2039/505A61K2039/545C07K16/286
Inventor KROEMER, GUIDOBRAVO-SAN, JOSÉ MANUEL
Owner INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)
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