Method for Reducing Levels of Disease Associated Proteins

• US 20100034745A1
• Filed: 07/08/2009
• Published: 02/11/2010
• Est. Priority Date: 05/03/2005
• Status: Abandoned Application

• Current Assignee: Accela Incorporated (Piksel Incorporated)
• Original Assignee: Neuera Pharmaceuticals, Inc. (Cerecin, Inc.)
• Inventors: Henderson, Samuel T.
• Application Number:
  US12/499,682
• Publication Number:
  US 20100034745A1
• Time in Patent Office: Days
• US Class Current: 424/9.200
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The subject invention concerns the reduction of protein aggregation in the neurons of a mammal through the use of a ketogenic treatment such as a ketogenic diet, a physical training regimen and/or administration of agents to increase fatty acid oxidation. Such ketogenic treatment can be useful in the reduction of certain aggregates including amyloid β peptide, polyglutamine containing huntintin protein, polyglutamine containing androgen receptor, polyglutamine containing atrophin-1, polyglutamine containing ataxins, α-synclein, prion protein, tau and superoxide dismutase 1 (SOD1).

Claims

1. A method of reducing protein aggregation in the brain of a mammal, said method comprising administering a ketogenic treatment so to produce ketosis or a ketogenic state in the mammal for a predetermined period, whereby the protein aggregation is reduced.

2. The method of claim 1, wherein the ketosis or ketogenic state comprises maintenance of a serum ketone body level elevated above normal fasting value.

3. The method of claim 2, wherein serum ketone level is above 0.2 mM, 0.3 mM, 0.4 mM or higher for one hour or more.

4. The method of claim 1, wherein the ketogenic treatment is dietary and comprises:

a) reducing dietary carbohydrates whereby serum insulin level and protein synthesis is reduced, while protein degradation is increased; and

b) increasing dietary lipids whereby cellular lipid metabolism is increased.

5. The method of claim 4, wherein the carbohydrate levels are restricted to an amount less than 20%, 10% or 2% of total calories and serum ketone levels are elevated above normal fasting baseline levels.

6. The method of claim 1, wherein the ketogenic treatment is induced by an agent that increases fatty acid oxidation.

7. The method of claim 6, wherein the agent that increases fatty acid oxidation is selected from the group consisting of L-carnitine and derivatives thereof, caffeine, ephedra alkaloids, non-steroidal anti-inflammatory agents (NSAIDs), statin drugs, and fibrates.

8. The method of claim 1, wherein the ketogenic treatment is induced by a physical training regimen.

9. The method of claim 8, wherein the physical training regimen comprises activity above 50% of either VO2max or maximal heart rate for a period of greater than 20 minutes.

10. The method of claim 1, wherein the ketogenic treatment is induced by a combination of at least two treatments selected from the group consisting of dietary treatment, fatty acid oxidation agent treatment, and physical training regimen.

11. The method of claim 10, wherein the dietary treatment is combined with the physical training regimen.

12. The method of claim 1, wherein the protein aggregates are selected from the group consisting of amyloid β

peptide, polyglutamine containing huntintin protein, polyglutamine containing androgen receptor, polyglutamine containing atrophin-1, polyglutamine containing ataxins, α

-synclein, prion protein, tau and superoxide dismutase 1 (SOD1).

13. The method of claim 1, further comprising administering a second compound which inhibits aggregate formation or is neuroprotective.

14. The method of claim 13, wherein the second compound is selected from the group consisting of Congo red, cystamine, cysteamine, minocycline, ethyl eicosapentaenoate, and riluzole.

15. The method of claim 1, wherein the ketogenic treatment is between 1 day and 1 year.

16. An assay for measuring the effectiveness of ketogenic treatment for the reduction or prevention of protein aggregation in cells, comprising

a) treating said cells in vivo or in vitro with a ketogenic treatment;

and

b) determining whether such treatment prevents or reduces protein aggregation in the cells.

17. The method of claim 16, wherein the reduction in protein aggregation is at least 25% by weight.

18. The assay of claim 16, wherein the in vivo treatment involves ketogenic treatment of a non-human mammal that exhibits neuronal aggregation of a protein associated with a protein aggregation disease under non-ketogenic conditions.

19. The assay of claim 16, wherein the non-human mammal is a transgenic mouse that exhibits neuronal protein aggregation under non-ketogenic conditions.

20. The assay of claim 16, wherein the in vitro treatment comprises ketogenic treatment of cultured cells which exhibit protein aggregation under non-ketogenic conditions.