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Methods of Treating Mitochondrial Dysfunction

a mitochondrial dysfunction and treatment method technology, applied in the field of mitochondrial dysfunction treatment methods, can solve the problems of tissue or organ dysfunction symptoms, drug side effects, and the effect of drugs only for a limited time period

Inactive Publication Date: 2014-03-06
ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE (EPFL)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes methods for treating disorders associated with mitochondrial dysfunction by administering compounds that increase intracellular nicotinamide adenine dinucleotide (NAD+) in an amount sufficient to activate SIRT1 or SIRT3. These methods may promote oxidative metabolism and increase the concentration of NAD+ within the mitochondria. The patent also describes methods of treating cancer by administering a PARP inhibitor and a NAD+ booster, or an AMPK agonist and a NAD+ booster. The NAD+ booster may include tryptophan, nicotinamide riboside (NR), niacin, or other compounds. The patent also mentions the use of other methods and materials for treating metabolic disorders and cancer.

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

Examples

Experimental program
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example 1

General Methods

[0097]Materials.

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

[0099]Animal Experiments.

[0100]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...

example 2

PARP-1− / − Mice are Leaner and Display Increased Energy Expenditure

[0158]A striking initial observation was that PARP-1− / − mice on chow weighed less (FIG. 1A) and accumulated less fat than wild-type (WT, PARP-1+ / +) littermates upon aging (FIG. 1B). This happened despite the fact that the PARP-1− / − mice consumed significantly more food (FIG. 1C). The effects of PARP-1 deletion on body mass and food intake were observed in both males and females (data not shown). During indirect calorimetry, PARP-1− / − mice also consumed more O2 (FIG. 1D), suggesting that their decreased body weight might be a consequence of increased energy expenditure (EE). Interestingly, resting energy expenditure (REE) was not different (FIG. 8), suggesting that the increase could be attributed to changes at night, when the mice are active. In line with this, spontaneous locomotor activity was significantly increased at night in PARP-1− / − mice (FIG. 8B). Consistently, the respiratory quotient was also higher in PARP...

example 3

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

[0160]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.

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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 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 which are each herein incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]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 diseases associated with aging.BACKGROUND OF THE INVENTION[0003]Mitochondria are cellular organelles present in most eukaryotic cells. One of their primary functions is oxidative phosphorylation, a process through which energy derived from metabolism of fuels like glucose or fatty acids is converted to ATP, which is then used to drive various energy-requiring biosynthetic reactions and other metabolic activities. Mitochondria have their own genom...

Claims

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Application Information

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IPC IPC(8): A61K31/706A61K45/06
CPCA61K45/06A61K31/706A61K31/05A61K31/405A61K31/473A61K31/502A61K31/7064A61K31/7088C12N15/1137C12N2310/14
Inventor ALVAREZ, CARLOS CANTOBAI, PETERHOUTKOOPER, RIEKELTAUWERX, JOHANMOUCHIROUD, LAURENT
Owner ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE (EPFL)
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