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Methods of treating mitochondrial dysfunction

a mitochondrial dysfunction and treatment method technology, applied in the direction of biochemistry apparatus and processes, organic active ingredients, dna/rna fragmentation, etc., can solve the symptoms of tissue or organ dysfunction, drug side effects, and the effect of drugs only for a limited time period

Inactive Publication Date: 2017-06-29
ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE (EPFL)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If a threshold proportion of mitochondria in a cell is defective, and if a threshold proportion of such cells within a tissue have defective mitochondria, symptoms of tissue or organ dysfunction can result.
While a number of drugs have been developed over the years to treat the various mitochondrial dysfunction, these drugs can often have side effects or are effective only for a limited time period.

Method used

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  • Methods of treating mitochondrial dysfunction
  • Methods of treating mitochondrial dysfunction
  • Methods of treating mitochondrial dysfunction

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example 1

General Methods

[0098]Materials. All chemicals, including PJ34 (Garcia et al., 2001), were from Sigma-Aldrich unless stated otherwise.

[0099]Animal Experiments. Male PARP-1+ / + and PARP-1− / − mice on a pure C57Bl / 6J background (Menissier-de Murcia et al., 1997) were used. Mice were housed separately, had ad libitum access to water and standard rodent chow (10 kcal % of fat, Safe, Augy, France) or to a high calorie, high fat diet (60 kcal % of fat, Research Diets, New Brunswick, N.J., USA), and were kept under a 12 h dark-light cycle. In other animal experiments, 8 weeks-old male C57Bl / 6J mice were purchased from Charles River and powder chow (D12450B) and high fat (D12492) diets were from Research Diets Inc (New Brunswick, N.J., USA). 80 ml of water per kg of powder CD were used to make food pellets. 40 ml of water per kg of powder HFD were used to make food pellets. For NR, NMN and NA supplemented diets, the appropriate amount of these compounds was added to the water used to create th...

example 3

PARP-1 Protein Levels and Activity are Regulated by Metabolic Challenges

[0133]The striking impact of PARP-1 deletion on metabolism made us wonder whether PARP activity would be dynamically regulated in normal mice upon physiological changes in nutrient availability. To test this hypothesis we analyzed whether nutrient scarcity (fasting) or overload (high-fat diet) would have an effect on PARP-1 activity. A 24-hr fast promoted a significant reduction in PARP activity, as manifested by the lower PARP-1 autoPARylation levels, which reflect global PARylation activity (Adamietz, 1987) (FIG. 2A). This change happened in the absence of changes in total PARP-1 levels, suggesting a lower activity of the enzyme (FIG. 2A). In contrast, nutrient overload induced by high-fat feeding promoted a robust increase in PARP-1 protein levels and PARP activity (FIG. 2B). Together, these data indicate that PARP-1 levels and activity are positively regulated by nutrient availability.

Example 4 PARP-1− / − Mic...

example 7 knocking -

Example 7 Knocking-Down PARP-1 in Cultured Cells Enhances Oxidative Metabolism

[0142]Given the effects of the somatic ablation of PARP-1 on SIRT1 activity and mitochondrial content in transgenic mice, we next evaluated whether reducing PARP-1 activity in an acute fashion could constitute a useful mechanism to increase cellular NAD+ levels and improve energy metabolism. For this purpose, we knocked-down PARP-1 expression in HEK293T cells. With this approach, we reduced PARP-1 protein levels by ˜80%, which dramatically reduced global intracellular PARP activity as manifested in the low auto-poly(ADP-ribosyl)ation of PARP-1 (FIG. 5A). The reduction of PARP activity in this cell model perfectly recapitulated all our in vivo findings. First of all, the reduction in PARP-1 activity increased the NAD+ content (FIG. 5B) and subsequently enhanced SIRT1 function, as evidenced by the strong decrease in PGC-1 acetylation levels (FIG. 5C). Importantly, this change happened in the absence of chang...

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Abstract

The present invention provides methods of treating various disorders associated with mitochondrial dysfunction, including but not limited to metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, and diseases of aging.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. Ser. No. 13 / 984,157, filed Nov. 20, 2013. U.S. Ser. No. 13 / 984,157 is a national stage application, filed under 35 U.S.C. §371, of International Application No. PCT / IB2012 / 001146, filed Feb. 15, 2012, which claims the benefit of provisional applications U.S. Ser. No. 61 / 443,052 filed Feb. 15, 2011 and U.S. Ser. No. 61 / 446,303, filed Feb. 24, 2011. The contents each of which are herein incorporated by reference in their entireties.INCORPORATION OF SEQUENCE LISTING[0002]The contents of the text file named “EPFL-003C01US_ST25.txt”, which was created on Oct. 12, 2016 and is 31 KB in size, are hereby incorporated by reference in their entiretyFIELD OF THE INVENTION[0003]The present invention relates generally to methods of increasing intracellular NAD+ for the treatment of various mitochondrial disorders, including but not limited to metabolic disorders, neurodegenerative diseases, and chronic inflammatory diseases, and...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/706A61K31/7088C12N15/113A61K45/06A61K31/473
CPCA61K31/706A61K45/06C12N2310/14C12N15/1137A61K31/7088A61K31/473A61K31/05A61K31/405A61K31/502A61K31/7064
Inventor ALVAREZ, CARLOS CANTOBAI, PETERHOUTKOOPER, RIEKELTAUWERX, JOHANMOUCHIROUD, LAURENT
Owner ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE (EPFL)
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