Methods and compositions for treating metabolic reprogramming disorders

A technology for reprogramming and disease, applied in drug combinations, active ingredients of phosphorus compounds, active ingredients of heterocyclic compounds, etc.

Active Publication Date: 2018-06-08
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, specific inhibitors of only individual enzymes in these metabolic pathways have not proven to be effective because as the metabolism of the cell is reprogrammed to meet the very large energy demands of an abnormal, harmful or unhealthy state, in each metabolic pathway Multiple points of the

Method used

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  • Methods and compositions for treating metabolic reprogramming disorders
  • Methods and compositions for treating metabolic reprogramming disorders
  • Methods and compositions for treating metabolic reprogramming disorders

Examples

Experimental program
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Effect test

Embodiment 1

[0392] Treatment of immune disorders

[0393] Glutamine analogs of the present disclosure were found to inhibit the antigen-specific effector CD4 in vivo + T cell proliferation and function ( Figure 1C , Figure 1D and Figure 1E ) and antigen-specific CD8 + T cell response ( Figure 2A , 2B and Figure 2C ). Addition of DON to metabolic reprogramming therapy results in very potent inhibition of CD4 + T cell effector function and CD8 + T cell effector functions.

[0394] To determine whether this inhibition of T cells by glutamine analogues could be used to reduce transplant rejection, skin from Balb / c mice was transplanted into B6 mice and treated with at least three metabolic reprogramming agents (e.g., 2DG + metformin +DON) or treated with DON alone ( image 3 ). The results showed that DON prevented graft rejection and prolonged skin graft survival. Furthermore, when hearts from Balb / c mice were transplanted into B6 mice, DON was found to be able to prevent...

Embodiment 2

[0397] Modulation of immune metabolism as the sole means of preventing allograft rejection

[0398] Summary

[0399] Upon antigen recognition and co-stimulation, T lymphocyte upregulation is a metabolic mechanism necessary for proliferation and maintenance of effector functions. Hallmarks of this response include a shift to aerobic glycolysis and an increased need for glutamine. This metabolic reprogramming in T cells is a key regulator of T cell activation and differentiation, not only as a result of antigen recognition. Furthermore, it is clear that while this metabolic reprogramming is important for the differentiation and function of T effector cells, the differentiation of regulatory T cells employs a different metabolic reprogramming. Based on these observations, it was hypothesized that inhibition of glycolysis and glutamine metabolism might represent a novel approach to prevent transplant rejection by inhibiting effector cell production and function while promoti...

Embodiment 3

[0433] Mice were sensitized to house dust mite antigen (HDM) in the absence of drugs. After intratracheal rechallenge, mice were treated with vehicle or 25. In this model, 25 suppressed pathology, recruitment / production of Th2 cells and reduced levels of HDM-specific IgE during acute lung rechallenge ( Figure 16 ). These data demonstrate the effectiveness of using DON prodrugs in the treatment of asthma.

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Abstract

The presently disclosed subject matter relates to metabolic reprogramming agents that decrease glutamine metabolism, glycolysis, and fatty acid synthesis, pharmaceutical compositions comprising at least one, at least two, or at least three metabolic reprogramming agents, and the use of those agents and compositions for treating metabolic reprogramming disorders, such as immune disorders (e.g., autoimmune diseases), inflammatory diseases, and transplant rejection, pathologies due to CNS inflammation due to infection and not involving infection, and neurodegenerative disorders.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Nos. 62 / 199,381 and 62 / 199,566, filed July 31, 2015, the contents of each of which are hereby incorporated by reference in their entirety. Background technique [0003] A cell may, under certain conditions, undergo a metabolic profile ranging from requiring less activity of certain metabolic pathways to meet the energy needs of the cell to requiring greater activity of these metabolic pathways or enhanced activity of other metabolic pathways to meet its energy needs Metabolic conversion of the metabolic profile required. For example, cells under certain conditions may undergo a switch towards increased glycolysis and away from oxidative phosphorylation (OXPHOS). Although glycolysis provides less adenosine triphosphate (ATP) than oxidative phosphorylation, it has been proposed that aerobic glycolysis allows for the production of substrates necessary for the g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/198A61K31/66A61K31/357A61K31/421A61K31/404A61K45/06
CPCA61K31/7076A61K39/39558A61K45/06A61K31/42A61K31/664A61K31/683A61K31/685A61K31/7034A61K35/17A61K31/655A61P35/00A61K31/22A61K31/225A61K31/4045Y02A50/30A61K2300/00A61K31/223A61K38/05A61K39/39541
Inventor 芭芭拉·斯卢谢尔乔纳森·鲍威尔
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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