Compositions and methods for treating pathological calcification and ossification
View Patent ↗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 reducing or preventing progression of pathological calcification in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a polypeptide comprising a soluble ecto-nucleotide pyrophosphate/phosphodiesterase-1 (NPP1) polypeptide, said soluble NPP1 polypeptide lacking a domain comprising 4 to 20 sequential aspartic acid residues, whereby pathological calcification in said subject is reduced or progression of pathological calcification in said subject is prevented.
2. The method of claim 1 , said soluble NPP1 polypeptide comprising a somatomedin B domain, an NPP1 catalytic domain, and an NPP1 nuclease domain.
3. The method of claim 1 , said soluble NPP1 polypeptide comprising residues 96-925 of human NPP1 [NCBI#006199, SEQ ID NO: 1].
4. The method of claim 1 , wherein said soluble NPP1 polypeptide is a secreted product of a precursor polypeptide expressed in a mammalian cell, wherein said precursor polypeptide comprises an ecto-nucleotide pyrophosphate/phosphodiesterase-2 (NPP2) signal sequence and NPP1, wherein said precursor polypeptide undergoes proteolytic processing to said soluble NPP1 polypeptide.
5. The method of claim 1 , wherein said soluble NPP1 polypeptide is a secreted product of a precursor polypeptide expressed in a mammalian cell, wherein said precursor polypeptide comprises residues 12-30 of NPP2 (NCBI accession no. NP_001124335, SEQ ID NO: 2), which is fused to the N-terminus of a polypeptide comprising a somatomedin B domain, an NPP1 catalytic domain, and an NPP1 nuclease domain, wherein said precursor polypeptide undergoes proteolytic processing to said soluble NPP1 polypeptide.
6. The method of claim 1 , wherein said soluble NPP1 polypeptide is a secreted product of a precursor polypeptide expressed in a mammalian cell, wherein said precursor polypeptide lacks residues 77-98 of the NPP1 transmembrane domain and comprises a signal sequence, wherein said precursor polypeptide undergoes proteolytic processing to said soluble NPP1 polypeptide.
7. The method of claim 1 , wherein said soluble NPP1 polypeptide is a secreted product of a precursor polypeptide expressed in a mammalian cell, wherein said precursor polypeptide comprises residues 1-76 of NPP1 (SEQ ID NO: 1), residues 12-30 of NPP2 (SEQ ID NO: 2), and residues 96-925 of NPP1 (SEQ ID NO: 1), wherein said precursor polypeptide undergoes proteolytic processing to said soluble NPP1 polypeptide.
8. The method of claim 1 , wherein said soluble NPP1 polypeptide is a fusion protein comprising an IgG Fc domain.
9. The method of claim 1 , wherein said soluble NPP1 polypeptide has ATP hydrolytic activity.
10. The method of claim 1 , wherein said polypeptide is administered acutely or chronically to the subject.
11. The method of claim 1 , wherein said polypeptide is administered locally, regionally, parenterally or systemically to the subject.
12. The method of claim 1 , wherein the subject is human.
13. The method of claim 1 , wherein pathological calcification is selected from the group consisting of idiopathic infantile arterial calcification (IIAC) and calcification of atherosclerotic plaques.