Methods for treatment of nephrotic syndrome and related conditions
The present disclosure provides a method for treating and/or preventing a condition characterized as a nephrotic syndrome, such as but not limited to minimal change disease (MCD) and membranous nephropathy (MN), and conditions related to nephrotic syndrome, such as but not limited to, proteinuria and edema, as well as diabetic nephropathy, diabetes mellitus, lupus nephritis or primary glomerular disease. The present disclosure further provides methods for reducing proteinuria and other disease states as discussed herein. Such methods comprise the therapeutic delivery of an Angptl4 polypeptide or Angptl4 polypeptide derivative to a subject.
1. A method for the treatment or reduction prior to onset of proteinuria in a subject, said method comprising the step of administering to the subject a therapeutically effective amount of an Angptl4 polypeptide selected from the group consisting of: positions 1-187 of SEQ ID NO: 1, positions 1-182 of SEQ ID NO: 3, and an Angptl4 derivative thereof; wherein the Angptl4 derivative thereof comprises one or more substitutions at positions 39, 40, 76, 80, and 161-164.
2. The method of claim 1 wherein the Angptl4 polypeptide comprises the sequence of SEQ ID NOS: 1 or 3.
3. The method of claim 1 , wherein the Angptl4 derivative has decreased lipoprotein lipase inhibitory activity, is resistant to cleavage, or a combination of the foregoing.
4. The method of claim 1 , wherein the Angptl4 derivative has decreased lipoprotein lipase inhibitory activity.
5. The method of claim 4 , wherein the Angptl4 derivative contains an amino acid substitution at position 40 with respect to the wild-type Angptl4 polypeptide.
6. The method of claim 5 , wherein the Angptl4 derivative contains K at position 40, A at position 40, K at position 39, A at position 39, or a combination of the foregoing.
7. The method of claim 1 , wherein the Angptl4 derivative is resistant to cleavage.
8. The method of claim 7 , wherein the Angptl4 derivative contains an amino acid substitution at one or more of positions 161, 162, 163 or 164 with respect to the wild-type Angptl4 polypeptide.
9. The method of claim 7 , wherein one or more of positions 161, 162 and 164 of the Angptl4 derivative is a neutral amino acid, and position 163 of the Angptl4 derivative is a neutral amino acid.
10. The method of claim 7 , wherein the residue at one or more of positions 161, 162 and 164 of the Angptl4 derivative is D, R, K, G, A, V or S; and the residue at position 163 of the Angptl4 derivative is D, R, K, G, A, V or S.
11. The method of claim 1 , wherein the Angptl4 derivative has the sequence of SEQ ID NOS: 9 or 10, wherein X 39 is D, X 40 is A or K, X 76 and X 80 are C, and X 161 , X 162 , X 163 and X 164 are independently selected from D, R, K, G, A; V or S.
12. The method of claim 1 , wherein the Angptl4 derivative has the sequence of SEQ ID NOS: 9 or 10; wherein X 39 is D; X 40 is A or K; one of X 76 and X 80 is A or S and the other of X 76 and X 80 is C and X 161 ; X 162 , X 163 and X 164 are independently selected from D, R, K, G, A, V or S.
13. The method of claim 1 , wherein the Angptl4 derivative has the sequence of SEQ ID NOS: 9 or 10; wherein X 39 is A or K; X 40 is E; X 76 and X 80 are C; and X 161 , X 162 , X 163 and X 164 are independently selected from D, R, K, G, A, V or S.
14. The method of claim 1 , wherein the Angptl4 derivative has the sequence of SEQ ID NOS: 9 or 10; wherein X 39 is A or K; X 40 is E; one of X 76 and X 80 is A or S and the other of X 76 and X 80 is C; and X 161 , X 162 , X 163 and X 164 are independently selected from D, R, K, G, A, V or S.
15. The method of claim 1 , wherein the Angptl4 derivative has the sequence of SEQ ID NOS: 9 or 10; wherein X 39 is D; X 40 is K; X 80 is C, or one of X 76 and X 80 is A or S and the other of X 76 and X 80 is C; and X 161 , X 162 , X 163 and X 164 are independently selected from D, R, K, G, A, V or S, provided that at least one of X 161 , X 162 , X 163 and X 164 is an amino acid not found in the corresponding positions of SEQ ID NOS: 1 or 3.
16. The method of claim 1 , wherein the Angptl4 derivative has the sequence of SEQ ID NOS: 9 or 10; wherein X 39 is K; X 40 is D; X 80 is C, or one of X 76 and X 80 is A or S and the other of X 76 and X 80 is C; and X 161 , X 162 , X 163 and X164 are independently selected from D, R, K, G, A, V or S.
17. The method of claim 1 , wherein the Angptl4 polypeptide is sialylated.
18. The method of claim 1 , in which the Angptl4 polypeptide is administered for at least two consecutive days.
19. The method of claim 1 , wherein said proteinuria is due to kidney disease.
20. The method of claim 1 , wherein said proteinuria is due to diabetic nephropathy or focal segmental glomerulosclerosis.