Compositions and methods for treating pathological calcification and ossification
The present invention includes compositions and methods for treating disease and disorders associated with pathological calcification or pathological ossification by modulating the level or activity of NPP1 or a mutant thereof, or a mutant NPP4 modified to exhibit ATP hydrolase activity similar to the hydrolase activity of NPP1.
1. A method of treating, reversing, or preventing progression of ossification of the posterior longitudinal ligament (OPLL) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a soluble ecto-nucleotide pyrophosphate/phosphodiesterase-1 (ENPP1) polypeptide, wherein the soluble ENPP1 polypeptide lacks a targeting domain, whereby ossification of the posterior longitudinal ligament (OPLL) in the subject is reduced or its progression is prevented or reversed.
2. The method of claim 1 , wherein the soluble ENPP1 polypeptide comprises the somatomedin B, catalytic, and nuclease domains of ENPP1.
3. The method of claim 1 , wherein the soluble ENPP1 polypeptide comprises residues 96-925 of human ENPP1 (SEQ ID NO: 1).
4. The method of claim 1 , wherein the soluble ENPP1 polypeptide is a cleavage product of a precursor ENPP1 polypeptide comprising an ecto-nucleotide pyrophosphate/phosphodiesterase-2 (ENPP2) signal sequence.
5. The method of claim 1 , wherein the soluble ENPP1 polypeptide is a cleavage product of a precursor ENPP1 polypeptide comprising residues 12-30 of ENPP2 (SEQ ID NO: 2) N-terminal to the somatomedin B, catalytic, and nuclease domains of ENPP1.
6. The method of claim 1 , wherein the soluble ENPP1 polypeptide is a cleavage product of a precursor ENPP1 polypeptide lacking residues 77-98 of the ENPP1 transmembrane domain and comprising a signal sequence.
7. The method of claim 1 , wherein the soluble ENPP1 polypeptide is a cleavage product of a precursor ENPP1 polypeptide comprising residues 1-76 of ENPP1 (SEQ ID NO: 1), residues 12-30 of ENPP2 (SEQ ID NO: 2), and residues 96-925 of ENPP1 sequence (SEQ ID NO: 1), wherein the precursor undergoes proteolytic processing to soluble ENPP1.
8. The method of claim 1 , wherein the targeting domain comprises 2 to 20 sequential aspartic acid residues.
9. The method of claim 1 , wherein the soluble ENPP1 polypeptide is a fusion protein comprising a fusion partner comprising an IgG Fc domain.
10. The method of claim 1 , wherein the soluble ENPP1 polypeptide has ATP hydrolytic activity.
11. The method of claim 1 , wherein the soluble ENPP1 polypeptide is administered acutely or chronically.
12. The method of claim 1 , wherein the soluble ENPP1 polypeptide is administered locally, regionally, parenterally, or systemically.
13. The method of claim 1 , wherein the subject is human.
14. A method of treating, reverting, or preventing progression of hypophosphatemic rickets in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a soluble ecto-nucleotide pyrophosphate/phosphodiesterase-1 (ENPP1) polypeptide, wherein the soluble ENPP1 lacks a targeting domain, whereby hypophosphatemic rickets in the subject is reduced or its progression is prevented or reversed.
15. The method of claim 14 , wherein the soluble ENPP1 polypeptide comprises the somatomedin B, catalytic, and nuclease domains of ENPP1.
16. The method of claim 14 , wherein the soluble ENPP1 polypeptide comprises residues 96-925 of human ENPP1 (SEQ ID NO: 1).
17. The method of claim 14 , wherein the soluble ENPP1 polypeptide is a cleavage product of a precursor ENPP1 polypeptide comprising an ecto-nucleotide pyrophosphate/phosphodiesterase-2 (ENPP2) signal sequence.
18. The method of claim 14 , wherein the soluble ENPP1 polypeptide is a cleavage product of a precursor ENPP1 polypeptide comprising residues 12-30 of ENPP2 (SEQ ID NO: 2) N-terminal to the somatomedin B, catalytic, and nuclease domains of ENPP1.
19. The method of claim 14 , wherein the soluble ENPP1 polypeptide is a cleavage product of a precursor ENPP1 polypeptide lacking residues 77-98 of the ENPP1 transmembrane domain and comprising a signal sequence.
20. The method of claim 14 , wherein the soluble ENPP1 polypeptide is a cleavage product of a precursor ENPP1 polypeptide comprising residues 1-76 of ENPP1 (SEQ ID NO: 1), residues 12-30 of ENPP2 (SEQ ID NO: 2), and residues 96-925 of ENPP1 sequence (SEQ ID NO: 1), wherein the precursor undergoes proteolytic processing to soluble ENPP1.
21. The method of claim 14 , wherein the targeting domain comprises 2 to 20 sequential aspartic acid residues.
22. The method of claim 14 , wherein the soluble ENPP1 polypeptide is a fusion protein comprising a fusion partner comprising an IgG Fc domain.
23. The method of claim 14 , wherein the soluble ENPP1 polypeptide has ATP hydrolytic activity.
24. The method of claim 14 , wherein the soluble ENPP1 polypeptide is administered acutely or chronically.
25. The method of claim 14 , wherein the soluble ENPP1 polypeptide is administered locally, regionally, parenterally, or systemically.