Methods for the treatment of X-linked hypophosphatemia and related disorders
The disclosure provides methods of treating X-linked hypophosphatemia, related bone demineralization and renal phosphate wasting disorders in a mammalian subject. The methods comprise administering to the subject an effective amount of a polyarginine peptide.
1. A method for increasing the activity of subtilisin-like protein convertase 2 (SPC2) in a hypophosphatemic mammalian subject in need thereof, comprising administering to the subject a therapeutically effective amount of a polyarginine peptide comprising at least four consecutive arginine residues, wherein the SPC2 activity is increased in the subject compared to a control subject not administered the polyarginine peptide.
2. The method of claim 1 , wherein the polyarginine peptide increases the expression of 7B2 mRNA in the subject compared to a control subject not administered the polyarginine peptide.
3. The method of claim 1 , wherein the polyarginine peptide increases the activity of the 7B2.SPC2 protein complex in the subject compared to a control subject not administered the polyarginine peptide.
4. The method of claim 1 , wherein FGF23and SOST mRNA expression are decreased in the subject compared to a control subject not administered the polyarginine peptide.
5. The method of claim 1 , wherein Npt2a mRNA expression or protein levels are increased in the subject compared to a control subject not administered the polyarginine peptide.
6. The method of claim 1 , wherein administering the polyarginine peptide increases serum phosphate in the subject compared to a control subject not administered the polyarginine peptide.
7. The method of claim 1 , wherein administering the polyarginine peptide increases degradation of serum FGF23 in the subject compared to a control subject not administered the polyarginine peptide.
8. The method of claim 1 , wherein the polyarginine peptide comprises from 5 to 16 arginine residues, and comprises L-arginine residues or D-arginine residues, or both.
9. The method of claim 1 , wherein the polyarginine peptide is selected from the group consisting of: penta-L-arginine (SEQ ID NO: 1), hexa-L-arginine (SEQ ID NO: 2), hepta-L-arginine (SEQ ID NO: 3), octa-L-arginine (SEQ ID NO: 4), nona-L-arginine (SEQ ID NO: 5), penta-D-arginine, hexa-D-arginine, hepta-D-arginine, octa-D-arginine, or nona-D-arginine, and combinations thereof.
10. The method of claim 1 , wherein the polyarginine peptide is hexa-L-arginine (SEQ ID NO: 2) or hexa-D-arginine, or both.
11. The method of claim 1 , wherein the polyarginine peptide lacks an N-terminal acetyl group, or wherein the polyarginine peptide lacks a C-terminal amide group, or wherein the polyarginine peptide lacks both an N-terminal acetyl group and a C-terminal amide group.
12. The method of claim 1 , wherein the polyarginine peptide is fused to a targeting agent.
13. The method of claim 12 , wherein the targeting agent is a bone targeting agent selected from the group consisting of bisphosphonate, a hydroxybisphosphonate, a phosphonate, a phosphate, an aminomethylenephosphonic acid, and an acidic peptide.
14. The method of claim 13 , wherein the bone targeting agent is covalently linked to the polyarginine peptide via a linker that is cleaved under physiological conditions.
15. The method of claim 14 , wherein the linker is(i) an acid-cleavable linker, (ii) selected from a group consisting of an enol ether, ketal, imine, oxime, hydrazone, semicarbazone, acylimide, and methylene radical, (iii) is a hydrolytically cleavable linker, or (iv) is cleaved enzymatically.
16. The method of claim 1 , wherein the polyarginine peptide is administered orally, topically, intranasally, intraperitoneally, intravenously, or subcutaneously.
17. A method for treating renal failure in a mammalian subject in need thereof, comprising administering to the subject a therapeutically effective amount of a polyarginine peptide comprising at least four consecutive arginine residues, wherein the polyarginine peptide is selected from the group consisting of: penta-L-arginine (SEQ ID NO: 1), hexa-L-arginine (SEQ ID NO: 2), hepta-L-arginine (SEQ ID NO: 3), octa-L-arginine (SEQ ID NO: 4), nona-L-arginine (SEQ ID NO: 5), penta-D-arginine, hexa-D-arginine, hepta-D-arginine, octa-D-arginine, or nona-D-arginine, and combination thereof.
18. The method of claim 17 , wherein administering the polyarginine peptide normalizes or decreases serum phosphate in the subject compared to a control subject not administered the polyarginine peptide.