Methods and compositions for treating hypercholesterolemia
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 - 36 . (canceled)
37 . A method for reducing plasma cholesterol in a mammal, without inducing hypertriglyceridemia, said method comprising administering to said mammal an effective amount of a nucleic acid encoding a therapeutic apoE protein, operably linked to a promoter that, when expressed in the target cells, is capable of expressing said therapeutic apoE protein, and wherein said therapeutic apoE protein comprises a naturally-occurring apoE protein having at least one amino acid substitution in the carboxy-terminal region.
38 . The method of claim 37 , wherein said nucleic acid is associated with a liposome.
39 . The method of claim 37 , wherein said nucleic acid is administered by intravenous injection.
40 . The method of claim 37 , wherein said nucleic acid comprises a recombinant viral vector.
41 . The method of claim 40 , wherein said vector is an adeno-associated vector, a lentiviral vector, a herpes viral vector, or a retroviral vector.
42 . The method of claim 37 , wherein said nucleic acid is administered to the liver.
43 . The method of claim 37 , 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.
44 . The method of claim 43 , wherein X is alanine.
45 . The method of claim 37 , wherein said therapeutic apoE protein comprises at least one amino acid substitution selected from the group consisting of L261A, W264A, F265A, L268A, and V269A.
46 . The method of claim 45 , wherein said therapeutic apoE protein comprises the amino acid substitutions L261A, W264A, F265A, L268A, and V269A.
47 . The method of claims 37 , wherein said naturally-occurring apoE protein is selected from the group consisting of apoE1, apoE2, apoE2*, apoE2**, apoE3, and apoE4 protein.
48 . The method of claim 37 , wherein said therapeutic apoE protein is apoE2[L261A/W264A/F265A/L268A/V269A].
49 . The method of claim 37 , wherein said therapeutic apoE protein is apoE3[L261A/W264A/F265A/L268A/V269A].
50 . The method of claim 37 , wherein said therapeutic apoE protein is apoE4[L261A/W264A/F265A/L268A/V269A].
51 . The method of claim 37 , 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.
52 . The method of claim 51 , wherein X is alanine.
53 . The method of claim 37 , wherein said therapeutic apoE protein comprises at least one amino acid substitution selected from the group consisting of W276A, L279A, V283A, V287A, and V293A.
54 . The method of claim 53 , wherein said therapeutic apoE protein comprises the amino acid substitutions W276A, L279A, V283A, V287A, and V293A.
55 . The method of claim 51 , wherein said therapeutic apoE protein is a therapeutic apoE1, apoE2, apoE2*, apoE2**, apoE3, or apoE4 protein.
56 . The method of claim 37 , wherein said therapeutic apoE protein is apoE2[W276A/L279A/V283A/V287A/V293A].
57 . The method of claim 37 , wherein said therapeutic apoE protein is apoE3[W276A/L279A/V283A/V287A/V293A].
58 . The method of claim 37 , wherein said therapeutic apoE protein is apoE4[W276A/L279A/V283A/V287A/V293A].
59 . A nucleic acid encoding a therapeutic apoE protein comprising a naturally-occurring apoE protein having at least one amino acid substitution in the carboxy-terminal region.
60 . A nucleic acid encoding the therapeutic apoE protein of claim 20 .
61 - 63 . (canceled)