Polyunsaturated fatty acids for treatment of dementia and pre-dementia-related conditions

• US 20070032548A1
• Filed: 07/07/2006
• Published: 02/08/2007
• Est. Priority Date: 07/08/2005
• Status: Abandoned Application

• Current Assignee: DSM IP Assets BV (DSM-Firmenich AG)
• Original Assignee: DSM IP Assets BV (DSM-Firmenich AG)
• Inventors: Ellis, Lorie
• Application Number:
  US11/483,138
• Publication Number:
  US 20070032548A1
• Time in Patent Office: Days
• US Class Current: 514/547
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/202 having three or more double bonds, e.g. linolenic eicosanoids, e.g. leukotrienes A61K31/557
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• 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

Disclosed are compositions and methods for treating or preventing dementia and pre-dementia-related conditions and/or symptoms or characteristics of such conditions.

Claims

1. A method to reduce the level of amyloid β

(Aβ

) peptide in an individual, comprising administering to an individual at least one polyunsaturated fatty acid (PUFA) or a precursor or source thereof to reduce the level of Aβ

peptide in the individual, wherein the PUFA is selected from the group consisting of;

docosahexaenoic acid (DHA);

docosapentaenoic acid (DPAn-6);

a combination of DHA and DPAn-6;

a combination of DHA and arachidonic acid (ARA); and

a combination of DHA, DPAn-6 and ARA.

2. The method of claim 1, wherein the Aβ

peptide is soluble Aβ

peptide.

15. The method of claim 1, wherein the individual is identified as being susceptible to or having dementia or pre-dementia.

16. The method of claim 15, wherein the dementia is Alzheimer'"'"'s disease.

17. The method of claim 15, wherein the individual is identified as having or being susceptible to dementia or pre-dementia by measurement of a biological marker, a family history showing dementia, mild cognitive impairment, or age-related cognitive decline.

18. The method of claim 17, wherein the biological marker is selected from the group consisting of APP, Aβ

peptide, tau protein, phosphorylated tau protein, PS1, and an omega-3 or an omega-6 polyunsaturated fatty acid (PUFA), or a precursor or source thereof.

19. The method of claim 17, wherein an amount, expression or biological activity of the biological marker is measured in a biological sample from the individual.

20. The method of claim 1, wherein, prior to the step of administering, the method comprises measuring an amount, expression or a biological activity of a biomarker selected from APP, Aβ

peptide, tau protein, phosphorylated tau protein, and PS1 protein in a biological sample from the individual.

21. The method of claim 20, further comprising comparing the amount, expression or biological activity of the biomarker in the individual sample to a baseline amount, expression or biological activity of the biomarker in a sample of the same type, wherein an increase in the amount, expression or biological activity of the biomarker in the individual sample, as compared to the baseline amount, expression or biological activity, indicates that the individual is at risk of developing or has dementia.

22. The method of claim 1, wherein, prior to the step of administering, the method comprises measuring an amount or biological activity of omega-3 or an omega-6 polyunsaturated fatty acid (PUFA), or a precursor or source thereof in a biological sample from the individual.

23. The method of claim 22, further comprising comparing an amount or biological activity of omega-3 or an omega-6 polyunsaturated fatty acid (PUFA), or a precursor or source thereof in the individual sample to a baseline amount or biological activity of the omega-3 or an omega-6 polyunsaturated fatty acid (PUFA), or a precursor or source thereof in a sample of the same type, wherein a change in the amount of the omega-3 or an omega-6 polyunsaturated fatty acid (PUFA), or a precursor or source thereof in the individual sample as compared to the baseline amount indicates that the individual is at risk of developing or has dementia.

24. The method of claim 20, wherein the step of measuring is performed by a method selected from the group consisting of:

Western blot, immunoblot, enzyme-linked immunosorbant assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, microcytometry, microarray, microscopy, fluorescence activated cell sorting (FACS), flow cytometry, capillary electrophoresis, protein microchip or microarray, fatty acid methyl esterification/gas chromatography, thin-layer chromatography, Gas chromatography/mass spectroscopy, and liquid chromatography/mass spectroscopy.

25. The method of claim 1, wherein the biological sample is selected from the group consisting of a cell sample, a tissue sample, and a bodily fluid sample.

26. The method of claim 25, wherein the biological sample is cerebrospinal fluid.

27. The method of claim 25, wherein the biological sample is a blood sample.

28. The method of claim 1, further comprising monitoring the efficacy of the administration of the PUFA on Aβ

peptide, tau protein, phosphorylated tau protein, or PS1 protein levels in the individual at least one time subsequent to the step of administering.

29. The method of claim 1, further comprising monitoring the efficacy of the administration of the PUFA on omega-3 or an omega-6 polyunsaturated fatty acid (PUFA) levels in the individual at least one time subsequent to the step of administering.

30. The method of claim 28, further comprising adjusting the administration of the PUFA to the individual in subsequent treatments based on the results of the monitoring of efficacy of the treatment.

31. The method claim 1, wherein the PUFA comprises a combination of DPAn-6 and DHA.

32. The method of claim 1, wherein the PUFA comprises a combination of ARA and DHA.

33. The method of claim 1, wherein the PUFA comprises a combination of DPAn-6, ARA and DHA.

34. The method of claim 1, wherein the PUFA comprises an oil comprising 30% or more of said PUFA, wherein the PUFA is in a chemical form selected from the group consisting of triglyceride form, triglyceride oil comprising the PUFA, phospholipids comprising the PUFA, a combination of protein and phospholipids comprising the PUFA, dried marine microalgae, sphingolipids comprising the PUFA, esters, as a free fatty acid, as a conjugate of the PUFA with another bioactive molecule, and combinations thereof.

35. The method of claim 1, wherein the PUFA comprises an oil comprising 40% or more of said PUFA, wherein the PUFAs are in a chemical form selected from the group consisting of triglyceride form, triglyceride oil comprising the PUFA, phospholipids comprising the PUFA, a combination of protein and phospholipids comprising the PUFA, dried marine microalgae, sphingolipids comprising the PUFA, esters, as a free fatty acid, as a conjugate of the PUFA with another bioactive molecule, and combinations thereof.

36. The method of claim 1, wherein the PUFA comprises an oil comprising 50% or more of said PUFA, wherein the PUFAs are in a chemical form selected from the group consisting of triglyceride form, triglyceride oil comprising the PUFA, phospholipids comprising the PUFA, a combination of protein and phospholipids comprising the PUFA, dried marine microalgae, sphingolipids comprising the PUFA, esters, as a free fatty acid, as a conjugate of the PUFA with another bioactive molecule, and combinations thereof.

37. The method of claim 1, wherein the PUFA comprises an oil comprising 60% or more of said PUFA, wherein the PUFAs are in a chemical form selected from the group consisting of triglyceride form, triglyceride oil comprising the PUFA, phospholipids comprising the PUFA, a combination of protein and phospholipids comprising the PUFA, dried marine microalgae, sphingolipids comprising the PUFA, esters, as a free fatty acid, as a conjugate of the PUFA with another bioactive molecule, and combinations thereof.

38. The method of claim 1, wherein the PUFA comprises an oil comprising 70% or more of said PUFA, wherein the PUFAs are in a chemical form selected from the group consisting of triglyceride form, triglyceride oil comprising the PUFA, phospholipids comprising the PUFA, a combination of protein and phospholipids comprising the PUFA, dried marine microalgae, sphingolipids comprising the PUFA, esters, as a free fatty acid, as a conjugate of the PUFA with another bioactive molecule, and combinations thereof.

39. The method of claim 1, wherein the PUFA comprises an oil comprising 80% or more of said PUFA, wherein the PUFAs are in a chemical form selected from the group consisting of triglyceride form, triglyceride oil comprising the PUFA, phospholipids comprising the PUFA, a combination of protein and phospholipids comprising the PUFA, dried marine microalgae, sphingolipids comprising the PUFA, esters, as a free fatty acid, as a conjugate of the PUFA with another bioactive molecule, and combinations thereof.

40. The method of claim 1, wherein the PUFA comprises DPAn-6 and DHA, and wherein the ratio of DPAn-6 to DHA is from about 1:

1 to about 1;

10.

41. The method of claim 1, wherein the PUFA comprises ARA and DHA, and wherein ratio of ARA to DHA is from about 1:

1 to about 1;

10.

42. The method of claim 1, wherein the PUFA comprises DPAn-6, ARA and DHA, and wherein the ratio of DPAn-6 to ARA to DHA is from about 1:

1;

1 to about 1;

1;

10.

43. The method of claim 1, wherein the PUFA is administered in an amount of from about 50 mg to about 20,000 mg per day.

44. The method of claim 1, wherein the PUFA is administered in an amount from about 0.025 mg to about 15 g per day.

45. The method of claim 1, wherein the PUFA is administered in an amount of from about 0.05 mg PUFA per kg body weight per day to about 275 mg PUFA per kg body weight per day.

46. The method of claim 1, wherein the PUFA is DHA.

47. The method of claim 1, wherein the source of the PUFA is selected from the group consisting of:

fish oil, marine microalgae, plant oil, and combinations thereof.

48. The method of claim 1, wherein the source of the PUFA is marine microalgae.

49. The method of claim 1, wherein the PUFA comprises DHA and wherein the precursor of DHA is selected from the group consisting of:

α

-linolenic acid (LNA);

eicosapentaenoic acid (EPA);

docosapentaenoic acid (DPA);

blends of LNA, EPA, or DPA.

50. The method of claim 1, wherein the PUFA is administered orally to the individual.

51. The method of claim 1, wherein the PUFA is administered to the individual as a formulation comprising the PUFA or precursor or source thereof selected from the group consisting of:

chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, granules, particles, microparticles, dispersible granules, cachets, douches, suppositories, creams, topicals, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, ingestibles, injectables, infusions, health bars, confections, cereals, cereal coatings, foods, nutritive foods, functional foods and combinations thereof.

52. The method of claim 51, wherein the PUFA in the formulation is provided in a form selected from the group consisting of:

a highly purified algal oil comprising the PUFA, triglyceride oil comprising the PUFA, phospholipids comprising the PUFA, a combination of protein and phospholipids comprising the PUFA, dried marine microalgae comprising the PUFA, sphingolipids comprising the PUFA, esters of the PUFA, free fatty acid, a conjugate of the PUFA with another bioactive molecule, and combinations thereof.

3. A method to reduce the level of tau protein in an individual, comprising administering to an individual at least one polyunsaturated fatty acid (PUFA) or a precursor or source thereof to reduce the level of tau protein in the individual, wherein the PUFA is selected from the group consisting of:

docosahexaenoic acid (DHA);

docosapentaenoic acid (DPAn-6);

a combination of DHA and DPAn-6;

a combination of DHA and arachidonic acid (ARA); and

a combination of DHA, DPAn-6 and ARA.

4. The method of claim 3, where the tau protein is phosphorylated tau protein.

5. A method to reduce the level of presenilin-1 (PS1) protein in an individual, comprising administering to an individual at least one polyunsaturated fatty acid (PUFA) or a precursor or source thereof to reduce the level of PS1 protein in the individual, wherein the PUFA is selected from the group consisting of:

docosahexaenoic acid (DHA);

docosapentaenoic acid (DPAn-6);

a combination of DHA and DPAn-6;

a combination of DHA and arachidonic acid (ARA); and

a combination of DHA, DPAn-6 and ARA.

6. A method to delay the onset of or reduce the severity of synaptic dysfunction in an individual, comprising administering to the individual DPAn-6 or a combination of polyunsaturated fatty acids (PUFAs) or precursors or sources thereof to delay the onset of or reduce the severity of synaptic dysfunction in the individual, wherein the combination of PUFAs is selected from the group consisting of:

a combination of DPAn-6 and DHA, a combination of ARA and DHA, and a combination of DPAn-6, ARA and DHA.

7. A method to delay the onset of or reduce the severity of dementia in an individual, comprising administering to an individual DPAn-6 or a combination of polyunsaturated fatty acids (PUFAs) or precursors or sources thereof to delay the onset of or reduce the severity of dementia in the individual, wherein the combination of PUFAs is selected from the group consisting of:

a combination of DPAn-6 and DHA, a combination of ARA and DHA, and a combination of DPAn-6, ARA and DHA.

8. A method to treat or prevent a disorder associated with increased amounts or expression of or dysfunction of amyloid β

(Aβ

) peptide, presenilin-1 (PS1) protein, phosphorylated tau protein, or tau protein, comprising;

a) identifying an individual having increased amount, expression, or biological activity of a biomarker selected from the group consisting of Aβ

peptide, PS1 protein, phosphorylated tau protein, tau protein, and combinations thereof, as compared to the amount, expression or biological activity of the biomarker in a negative control individual; and

b) administering to the individual at least one polyunsaturated fatty acid (PUFA) or a precursor or source thereof to reduce the amount, expression or biological activity of the Aβ

peptide, PS1 protein, phosphorylated tau protein, or tau protein, wherein the PUFA is selected from the group consisting of;

docosahexaenoic acid (DHA);

docosapentaenoic acid (DPAn-6);

a combination of DHA and DPAn-6;

a combination of DHA and arachidonic acid (ARA); and

a combination of DHA, DPAn-6 and ARA.

9. A method to treat or prevent a disorder associated with decreased amounts of omega-3 or omega-6 polyunsaturated fatty acid (PUFA) or a precursor or source thereof, comprising:

a) identifying an individual with decreased amounts of omega-3 or omega-6 polyunsaturated fatty acid (PUFA) or a precursor or source thereof; and

b) administering to the individual a combination of polyunsaturated fatty acids (PUFAs) or precursors or sources thereof to compensate for the effects of the decreased amounts of omega-3 or omega-6 polyunsaturated fatty acid (PUFA) or a precursor or source thereof, wherein the combination of PUFAs is selected from the group consisting of;

a combination of DPAn-6 and DHA, a combination of ARA and DHA, and a combination of DPAn-6, ARA and DHA.

10. A method to delay the onset of or reduce the severity of a decline in brain function in an individual comprising administering to the individual DPAn-6 or a combination of polyunsaturated fatty acids (PUFAs) or precursors or sources thereof, to delay the onset of or reduce the severity of a decline in the brain function in the individual, wherein the combination of PUFAs is selected from the group consisting of:

a combination of DPAn-6 and DHA, a combination of ARA and DHA, and a combination of DPAn-6, ARA and DHA.

11. The method of claim 10, wherein brain function is measured by a method selected from the group consisting of neuropsychological or cognitive tests, brain imaging methods (PET, SPECT, CT, MRI, fMRI), and electroencephalography (EEG).

12. A method to delay or reduce the severity of demyelination in an individual comprising administering to the individual DPAn-6 or a combination of polyunsaturated fatty acids (PUFAs) or precursors or sources thereof, to delay or reduce the severity of demyelination in the individual, wherein the combination of PUFAs is selected from the group consisting of:

a combination of DPAn-6 and DHA, a combination of ARA and DHA, and a combination of DPAn-6, ARA and DHA.

13. A method to delay the onset of or reduce the severity of neurofibrillary tangles associated with Alzheimer'"'"'s Disease in an individual, comprising administering to the individual DPAn-6 or a combination of polyunsaturated fatty acids (PUFAs) or precursors or sources thereof, to delay the onset of or reduce the severity of neurofibrillary tangles in the individual, wherein the combination of PUFAs is selected from the group consisting of:

a combination of DPAn-6 and DHA, a combination of ARA and DHA, and a combination of DPAn-6, ARA and DHA.

14. A method to stabilize or normalize theta wave activity or to reduce or prevent the development of abnormal theta wave activity in an individual, comprising:

a) identifying an individual that has or is predicted to develop abnormal theta wave activity; and

b) administering to the individual at least one polyunsaturated fatty acid (PUFA) or a precursor or source thereof to stabilize or normalize theta wave activity or to prevent or reduce the development of abnormal theta wave activity in an individual, wherein the PUFA is selected from the group consisting of;

docosahexaenoic acid (DHA);

docosapentaenoic acid (DPAn-6);

a combination of DHA and DPAn-6;

a combination of DHA and arachidonic acid (ARA); and

a combination of DHA, DPAn-6 and ARA.

53. A pharmaceutical composition comprising a combination of polyunsaturated fatty acids (PUFAs) or precursors or sources thereof, and at least one therapeutic compound for treatment or prevention of dementia in an individual that has or is at risk of developing dementia, wherein the combination of PUFAs is selected from the group consisting of DPAn-6 and DHA, ARA and DHA, and DPAn-6, ARA and DHA.

54. The composition of claim 53, wherein the combination of PUFAs comprises an oil comprising 30% or more of said PUFA, wherein the PUFA is in a chemical form selected from the group consisting of triglyceride form, triglyceride oil comprising the PUFA, phospholipids comprising the PUFA, a combination of protein and phospholipids comprising the PUFA, dried marine microalgae, sphingolipids comprising the PUFA, esters, as a free fatty acid, as a conjugate of the PUFA with another bioactive molecule, and combinations thereof.

55. The composition of claim 53, wherein the combination of PUFAs comprises an oil comprising 80% or more of said PUFA, wherein the PUFA is in a chemical form selected from the group consisting of triglyceride form, triglyceride oil comprising the PUFA, phospholipids comprising the PUFA, a combination of protein and phospholipids comprising the PUFA, dried marine microalgae, sphingolipids comprising the PUFA, esters, as a free fatty acid, as a conjugate of the PUFA with another bioactive molecule, and combinations thereof.

56. The composition of claim 53, wherein the source of the PUFA is selected from the group consisting of:

fish oil, marine algae, plant oil, and combinations thereof.

57. The composition of claim 53, wherein the source of the PUFA is marine microalgae.

58. The composition of claim 53, wherein the precursor of DHA is selected from the group consisting of:

α

-linolenic acid (LNA);

eicosapentaenoic acid (EPA);

docosapentaenoic acid (DPA);

blends of LNA, EPA, or DPA.

59. The composition of claim 53, wherein the PUFA is provided in a formulation selected from the group consisting of:

chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, granules, particles, microparticles, dispersible granules, cachets, douches, suppositories, creams, topicals, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, ingestibles, injectables, infusions, health bars, confections, cereals, cereal coatings, foods, nutritive foods, functional foods and combinations thereof.

60. The composition of claim 59, wherein the PUFA in the formulation is provided in a form selected from the group consisting of:

a highly purified algal oil comprising the PUFA, triglyceride oil comprising the PUFA, phospholipids comprising the PUFA, a combination of protein and phospholipids comprising the PUFA, dried marine microalgae comprising the PUFA, sphingolipids comprising the PUFA, esters of the PUFA, free fatty acid, a conjugate of the PUFA with another bioactive molecule, and combinations thereof.

61. The composition of claim 53, wherein the therapeutic compound is selected from the group consisting of a protein, an amino acid, a drug, and a carbohydrate.

62. The composition of claim 53, wherein the therapeutic compound is selected from the group consisting of:

tacrine;

donepezil;

rivastigmine;

galantamine;

memantine;

neotropin;

nootropics;

alpha-tocopherol (vitamin E);

selegeline;

non-steroidal anti-inflammatory agents (NSAIDS);

gingko biloba;

estrogen;

β

-secretase inhibitors;

vaccines;

B complex vitamins;

calcium channel blockers;

HMG CoA reductase inhibitors;

statins;

policosanols;

fibrates;

clioquinol;

curcumin;

lignans;

phytoestrogens;

phytosterols;

niacin; and

vitamin supplements. The use of at least one polyunsaturated fatty acid (PUFA) or a precursor or source thereof in the preparation of a composition, wherein the PUFA is selected from the group consisting of;

docosahexaenoic acid (DHA);

docosapentaenoic acid (DPAn-6);

a combination of DHA and DPAn-6;

a combination of DHA and arachidonic acid (ARA); and

a combination of DHA, DPAn-6 and ARA;

wherein the composition is for;

reducing the level of amyloid β

(Aβ

) peptide in an individual;

reducing the level of tau protein in an individual;

reducing the level of presenilin-1 (PS1) protein in an individual;

treating or preventing a disorder associated with increased amounts or expression of or dysfunction of amyloid β

(Aβ

) peptide, presenilin-1 (PS1) protein, phosphorylated tau protein, or tau protein;

or stabilizing or normalizing theta wave activity or reducing or preventing the development of abnormal theta wave activity in an individual.

63. The use of at least one polyunsaturated fatty acid (PUFA) or a precursor or source thereof in the preparation of a composition, wherein the PUFA is selected from the group consisting of:

docosapentaenoic acid (DPAn-6);

a combination of DHA and DPAn-6;

a combination of DHA and arachidonic acid (ARA); and

a combination of DHA, DPAn-6 and ARA;

wherein the composition is for;

delaying the onset of or reduce the severity of synaptic dysfunction in an individual;

delaying the onset of or reduce the severity of dementia in an individual;

treating or preventing a disorder associated with decreased amounts of omega-3 or omega-6 polyunsaturated fatty acid (PUFA);

delaying the onset of or reducing the severity of a decline in brain function in an individual;

delaying or reducing the severity of demyelination in an individual;

delaying the onset of or reducing the severity of neurofibrillary tangles associated with Alzheimer'"'"'s Disease in an individual.