Methods for treatment of nephrotic syndrome and related conditions
The present disclosure provides a method for treating and/or preventing nephrotic syndrome, such as but not limited to minimal change disease and membranous nephropathy, 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 the reduction prior to onset of proteinuria in a subject in need thereof, said method comprising administering to the subject in a therapeutically effective amount a pharmaceutical composition comprising an Angptl4 polypeptide derivative having decreased LPL inhibitory activity, the Angptl4 polypeptide derivative comprising the following structure:
V-W-X-Y-Z
wherein
V is a sequence having at least 95% homology with SEQ ID NO: 23, wherein positions 40 is K, A, or E;
W is an oligopeptide of 0-5 residues;
X is a sequence having at least 95% homology with SEQ ID NO: 24;
Y is an oligopeptide of 0-38 residues; and
Z is a sequence having at least 95% homology with SEQ ID NO: 25.
2. The method of claim 1 , wherein positions 39-40 of V is not DE, position 46 of V is not H, position 50 of V is not Q, and position 53 of V is not Q.
3. The method of claim 1 , wherein the sequence at positions 39-40 of SEQ ID NO: 23 is not DE.
4. The method of claim 1 , wherein position 39 of SEQ ID NO: 23 is a positively charged residue or a neutral residue.
5. The method of claim 1 , wherein position 40 of SEQ ID NO: 23 is a negatively charged residue or a neutral residue.
6. The method of claim 1 , wherein position 39 of SEQ ID NO: 23 is K or A.
7. The method of claim 1 , wherein position 39 of SEQ ID NO: 23 is K or A.
8. The method of claim 1 , wherein the sequence at positions 39 and 40 of SEQ ID NO: 23 is selected from the group consisting of DK, KE, DA, and AE.
9. The method of claim 1 , wherein the sequence at positions 63-66 of SEQ ID NO: 24 is not RRKR, and wherein the Angptl4 polypeptide has increased resistance to cleavage.
10. The method of claim 9 , wherein one or more of positions 63-66 of SEQ ID NO: 24 are independently selected from the group consisting of D, R, K, G, A, V, and S.
11. The method of claim 9 , wherein all of positions 63-66 of SEQ ID NO: 24 are independently selected from the group consisting of D, R, K, G, A, V, and S.
12. The method of claim 9 , wherein one or more of positions 63-66 of SEQ ID NO: 24 are independently selected from the group consisting of G, A, S, and V.
13. The method of claim 9 , wherein all of positions 63-66 of SEQ ID NO: 24 are independently selected from the group consisting of G, A, S, and V.
14. The method of claim 9 , wherein the sequence at positions 63-66 of SEQ ID NO: 24 is selected from the group consisting of: SEQ ID NOS: 29-90.
15. The method of claim 9 , wherein the sequence at positions 63-66 of SEQ ID NO: 24 is selected from the group consisting of GAAG (SEQ ID NO: 29), GSGS (SEQ ID NO: 80), GVVA (SEQ ID NO: 49), SGGG (SEQ ID NO: 87), and VAVA (SEQ ID NO: 90).
16. The method of claim 9 , wherein of the sequence at positions 63-66 of SEQ ID NO: 24 is selected from GSGS (SEQ ID NO: 80), SGGG (SEQ ID NO: 87), and GVVA (SEQ ID NO: 49).
17. The method of claim 1 , wherein the sequence at positions 39-40 of SEQ ID NO: 23 is DK and the sequence at positions 63-66 of SEQ ID NO: 24 is GSGS (SEQ ID NO: 80).
18. The method of claim 1 , wherein the sequence at positions 39-40 of SEQ ID NO: 23 is KE and the sequence at positions 63-66 of SEQ ID NO: 24 is SGGG (SEQ ID NO: 87).
19. The method of claim 1 , wherein the sequence at positions 39-40 of SEQ ID NO: 23 is DA and the sequence at positions 63-66 of SEQ ID NO: 24 is GVVA (SEQ ID NO: 49).
20. The method of claim 1 , wherein said structure is:
A-B-C
wherein
A has at least 95% homology with SEQ ID NO: 26, wherein the sequence at position 40 is K, A, or E;
B is an oligopeptide of 0-38 residues; and
C has at least 95% homology with SEQ ID NO: 27.
21. The method of claim 1 , wherein the Angptl4 polypeptide derivative has at least 95% sequence homology with SEQ ID NO: 9.
22. The method of claim 1 , wherein the Angptl4 polypeptide derivative has at least 95% homology with SEQ ID NO: 10.
23. The method of claim 1 , wherein the Angptl4 polypeptide derivative is sialylated.
24. The method of claim 1 , comprising administering the pharmaceutical composition to the subject at a dosage of about 0.05-150,000 μg/kg.
25. The method of claim 1 , comprising administering the pharmaceutical composition to the subject at a dosage of about 50-150 μg/kg.
26. The method of claim 1 , comprising administering the pharmaceutical composition to the subject once per 14 days ±20%.
27. The method of claim 1 , comprising administering the pharmaceutical composition to the subject twice per month ±20%.
28. The method of claim 1 , comprising administering the pharmaceutical composition to the subject from once per month to twice per month, ±20%.
29. The method of claim 1 , comprising a step to deliver the Angptl4 polypeptide derivative to the subject's blood.
30. The method of claim 1 , comprising administering the pharmaceutical composition to the subject intravenously.
31. The method of claim 1 , wherein the proteinuria is a result of minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy/membranous glomerulonephritis, membranoproliferative glomerulonephritis or a diabetic condition.
32. The method of claim 1 , wherein the proteinuria is caused by minimal change disease.
33. The method of claim 1 , wherein the proteinuria is a result of diabetic nephropathy, diabetes mellitus, lupus nephritis or primary glomerular disease.
34. The method of claim 9 , wherein the sequence at positions 63-66 of SEQ ID NO: 24 is VAVA (SEQ ID NO: 90).
35. The method of claim 1 , wherein said proteinuria is due to kidney disease.
36. The method of claim 1 , wherein said proteinuria is due to diabetic nephropathy or focal segmental glomerulosclerosis.