Method of treating and preventing alzheimer disease through administration of delipidated protein and lipoprotein particles

• US 20040106556A1
• Filed: 08/26/2003
• Published: 06/03/2004
• Est. Priority Date: 08/26/2002
• Status: Abandoned Application

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Zhu, Yanhong, Maltais, Jo-Ann B., Cham, Bill E.
• Application Number:
  US10/650,110
• Publication Number:
  US 20040106556A1
• Time in Patent Office: Days
• US Class Current: 514/12
• 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 38/1709 from mammals
• 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

Abstract

The present invention relates to a method for preventing, reducing the progression of, and treating Alzheimer disease (AD), by creating delipidated protein particles and lipoprotein particles including at least one of LDL, VLDL, or HDL, other particles associated with lipid transport and metabolism, and combinations thereof, and administering these delipidated particles to patients at risk of developing AD or patients diagnosed with AD. The present invention employs energy and solvents useful for extracting lipids and cholesterol from the lipid-containing plasma and forming delipidated protein particles and lipoprotein particles. The present invention uses optimal solvent systems such that the lipid is dissolved while other plasma proteins are relatively intact. The present invention also provides a method of combining plasma delipidation and particle administration with other therapeutic interventions for prevention and treatment of AD.

Claims

1. A composition effective to prevent or delay the onset of Alzheimer disease in a patient at risk of developing Alzheimer disease comprising one or more partially delipidated protein particles, one or more partially delipidated lipoprotein particles or a combination thereof.

3. The composition of claim 1, wherein the one or more partially delipidated protein particles or the one or more partially delipidated lipoprotein particles are HDL, LDL or VLDL, or a combination thereof.

5. The composition of claim 1, wherein the one or more partially delipidated protein particles or the one or more partially delipidated lipoprotein particles are prepared by a process comprising:

obtaining blood containing lipid from the patient;

separating cells from the blood to form plasma containing lipid, protein particles and lipoprotein particles;

contacting the plasma containing the lipid and the particles with a first organic solvent capable of extracting lipid;

mixing the fluid and the first organic solvent;

permitting organic and aqueous phases to separate;

collecting the aqueous phase containing reduced lipid content, wherein the aqueous phase contains the one or more partially delipidated protein particles or the one or more partially delipidated lipoprotein particles.

2. A composition effective to treat Alzheimer disease in a patient with Alzheimer disease comprising one or more partially delipidated protein particles, one or more partially delipidated lipoprotein particles or a combination thereof.

4. The composition of claim 2, wherein the one or more partially delipidated protein particles or the one or more partially delipidated lipoprotein particles are HDL, LDL or VLDL, or a combination thereof.

6. The composition of claim 2, wherein the one or more partially delipidated protein or lipoprotein particles are prepared by a process comprising:

obtaining blood containing lipid from the patient;

separating cells from the blood to form plasma containing lipid, protein particles and lipoprotein particles;

contacting the plasma containing the lipid and the particles with a first organic solvent capable of extracting lipid;

mixing the fluid and the first organic solvent;

permitting organic and aqueous phases to separate;

collecting the aqueous phase containing reduced lipid content, wherein the aqueous phase contains the one or more partially delipidated protein particles or the one or more partially delipidated lipoprotein particles.

7. A method for treating Alzheimer disease in a patient diagnosed with Alzheimer disease comprising:

administration of an effective amount of one or more partially delipidated protein particles, one or more partially delipidated lipoprotein particles or a combination thereof, wherein the amount is effective to treat Alzheimer disease in the patient.

9. The method of claim 7, wherein the one or more partially delipidated lipoprotein particles is HDL, LDL or VLDL, or a combination thereof.

11. The method of claim 7, wherein the method reduces amyloid plaque, decreases neurofibrillary tangles, reduces levels of A#, alters a ratio of Aβ

40 to Aβ

42, affects enzymatic processing of APP, or reduces levels of phosphorylated tau protein.

13. The method of claim 7, further comprising administration of a therapeutic agent, wherein the therapeutic agent is an agent that affects lipid metabolism or is an agent that affects parameters associated with Alzheimer disease.

15. The method of claim 13, wherein the therapeutic agent is a selected from the group consisting of synthetic HDL compositions, compositions selectively enhancing HDL function with minimal effect on LDL levels, cholesteryl ester transfer protein inhibitors, cholesterol level lowering agents and triglyceride level lowering agents in a pharmaceutically acceptable vehicle, and combinations thereof.

8. A method for preventing or delaying the onset of Alzheimer disease in a patient at risk of developing Alzheimer disease comprising:

administration of an effective amount of one or more partially delipidated protein particles, one or more partially delipidated lipoprotein particles or a combination thereof, wherein the amount is effective to prevent or delay the onset of Alzheimer disease in the patient.

10. The method of claim 8, wherein the one or more partially delipidated lipoprotein particles is HDL, LDL or VLDL, or a combination thereof.

12. The method of claim 8, wherein the method reduces amyloid plaque, decreases neurofibrillary tangles, reduces levels of Aβ

, alters a ratio of Aβ

40 to Aβ

42, affects enzymatic processing of APP, or reduces levels of phosphorylated tau protein.

14. The method of claim 8, further comprising administration of a therapeutic agent, wherein the therapeutic agent is an agent that affects lipid metabolism or is an agent that affects parameters associated with Alzheimer disease.

16. The method of claim 14, wherein the therapeutic agent is a selected from the group consisting of synthetic HDL compositions, compositions selectively enhancing HDL function with minimal effect on LDL levels, cholesteryl ester transfer protein inhibitors, cholesterol level lowering agents and triglyceride level lowering agents in a pharmaceutically acceptable vehicle, and combinations thereof.