Methods and compositions for treating hypercholesterolemia
View Patent ↗The present invention provides methods and compositions for treating hypercholesterolemia using therapeutic apoE proteins. A therapeutic apoE protein is a naturally-occurring apoE protein (e.g., apoE1, apoE2, apoE2*, apoE2**, apoE3, and apoE4) that has one or more amino acid substitutions in the carboxy-terminal region which, when administered to a mammal having hypercholesterolemia, reduces the plasma cholesterol levels without inducing hypertriglyceridemia. The invention also provides a method for reducing plasma cholesterol using low doses of naturally-occurring apoE proteins.
1. A method for reducing plasma cholesterol in a mammal, without inducing hypertriglyceridemia, said method comprising administering to said mammal a therapeutic apoE protein comprising a sequence having at least 95% sequence identity to SEQ ID NO: 1 and at least one amino acid substitution in the carboxy-terminal region.
2. The method of claim 1 , wherein said mammal is a human.
3. The method of claim 1 , wherein said therapeutic apoE protein comprises at least one amino acid substitution selected from the group consisting of L261X, W264X, F265X, L268X, and V269X, wherein X is any amino acid.
4. The method of claim 3 , wherein X is alanine.
5. The method of claim 1 , wherein said therapeutic apoE protein comprises at least one amino acid substitution selected from the group consisting of L261A, W264A, F265A, L268A, and V269A.
6. The method of claim 5 , wherein said therapeutic apoE protein comprises the amino acid substitutions L261A, W264A, F265A, L268A, and V269A.
7. The method of claim 1 , wherein said therapeutic apoE protein is apoE4.
8. The method of claim 1 , wherein said therapeutic apoE protein comprises at least one amino acid substitution selected from the group consisting of W276X, L279X, V283X, V287X, and V293X, wherein X is any amino acid.
9. The method of claim 8 , wherein X is alanine.
10. The method of claim 1 , wherein said therapeutic apoE protein comprises at least one amino acid substitution selected from the group consisting of W276A, L279A, V283A, V287A, and V293A.
11. The method of claim 10 , wherein said therapeutic apoE protein comprises the amino acid substitutions W276A, L279A, V283A, V287A, and V293A.
12. The method of claim 1 , wherein said therapeutic apoE protein is apoE4.
13. The method of claim 1 , wherein said therapeutic apoE protein is administered by intravenous injection.
14. A therapeutic apoE protein comprising a sequence having at least 95% sequence identity to SEQ ID NO: 1 and at least one amino acid substitution in the carboxy-terminal region, wherein said protein when administered to a mammal is capable of lowering the total serum cholesterol levels without inducing hypertriglyceridemia.
15. The therapeutic apoE protein of claim 14 , wherein said therapeutic apoE protein comprises at least one amino acid substitution selected from the group consisting of L261X, W264X, F265X, L268X, and V269X, wherein X is any amino acid.
16. The therapeutic apoE protein of claim 15 , wherein X is alanine.
17. The therapeutic apoE protein of claim 14 , wherein said therapeutic apoE protein comprises at least one amino acid substitution selected from the group consisting of L261A, W264A, F265A, L268A, and V269A.
18. The therapeutic apoE protein of claim 17 , wherein said therapeutic apoE protein comprises the amino acid substitutions L261A, W264A, F265A, L268A, and V269A.
19. The therapeutic apoE protein of claim 14 , wherein said therapeutic apoE protein is apoE4.
20. The therapeutic apoE protein of claim 14 , wherein said therapeutic apoE protein comprises at least one amino acid substitution selected from the group consisting of W276X, L279X, V283X, V287X, and V293X, wherein X is any amino acid.
21. The therapeutic apoE protein of claim 20 , wherein X is alanine.
22. The therapeutic apoE protein of claim 1 , wherein said therapeutic apoE protein comprises at least one amino acid substitution selected from the group consisting of W276A, L279A, V283A, V287A, and V293A.
23. The therapeutic apoE protein of claim 22 , wherein said therapeutic apoE protein comprises the amino acid substitutions W276A, L279A, V283A, V287A, and V293A.
24. The therapeutic apoE protein of claim 14 , wherein said therapeutic apoE protein is apoE4.
25. The therapeutic apoE protein of claim 17 , wherein said therapeutic apoE protein comprises the amino acid substitutions L261A, W264A, and F265A.