Compositions for treating pathological calcification conditions, and methods using same
The present invention includes compositions and methods for treating diseases or disorders associated with pathological calcification or pathological ossification. In certain embodiments, the diseases or disorders are selected from the group consisting of Generalized Arterial Calcification of Infancy (GACI), Idiopathic Infantile Arterial Calcification (IIAC), Ossification of the Posterior Longitudinal Ligament (OPLL), hypophosphatemic rickets, osteoarthritis, calcification of atherosclerotic plaques, PXE, hereditary and non-hereditary forms of osteoarthritis, ankylosing spondylitis, hardening of the arteries occurring with aging, calciphylaxis resulting from end stage renal disease and progeria.
1. A method of reducing or preventing progression of aging related hardening of arteries 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 (ENPP1) polypeptide, wherein the soluble ENPP1 polypeptide lacks a bone-targeting sequence, whereby aging related hardening of arteries in the subject is reduced or its progression is prevented.
2. The method of claim 1 , wherein the soluble ENPP1 polypeptide comprises a somatomedin B domain, an ENPP1 catalytic domain, and an ENPP1 nuclease domain.
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 secreted product of a precursor polypeptide expressed in a mammalian cell, wherein the precursor polypeptide comprises a signal peptide and ENPP1, wherein the precursor polypeptide undergoes proteolytic processing to the soluble ENPP1 polypeptide.
5. The method of claim 4 , wherein the soluble ENPP1 polypeptide is a secreted product of a precursor polypeptide expressed in a mammalian cell, wherein the precursor polypeptide comprises an ecto-nucleotide pyrophosphate/phosphodiesterase- 2 (ENPP2) signal peptide, which is fused to the N-terminus of a polypeptide comprising a somatomedin B domain, an ENPP1 catalytic domain, and an ENPP1 nuclease domain, wherein the precursor polypeptide undergoes proteolytic processing to the soluble ENPP1 polypeptide.
6. The method of claim 5 , wherein the soluble ENPP1 polypeptide is a secreted product of a precursor polypeptide expressed in a mammalian cell, wherein the precursor polypeptide comprises residues 1-76 of ENPP1 (SEQ ID NO: 1), residues 12-30 of ENPP2 (SEQ ID NO: 2), and residues 96-925 of ENPP1 (SEQ ID NO: 1), wherein the precursor polypeptide undergoes proteolytic processing to the soluble ENPP1 polypeptide.
7. The method of claim 4 , wherein the signal peptide comprises ENPP2 signal peptide or ecto-nucleotide pyrophosphate/phosphodiesterase-7 (ENPP7) signal peptide.
8. The method of claim 1 , wherein the soluble ENPP1 polypeptide is a secreted product of a precursor polypeptide expressed in a cell, wherein the precursor polypeptide lacks residues 77-98 of the ENPP1 (SEQ ID NO: 1) transmembrane domain and comprises a signal peptide, wherein the precursor polypeptide undergoes proteolytic processing to the soluble ENPP1 polypeptide.
9. The method of claim 1 , wherein the subject is human.
10. The method of claim 1 , wherein the polypeptide is administered to the subject as a pharmaceutical composition further comprising at least one excipient.
11. The method of claim 1 , wherein the polypeptide is administered to the subject as a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.
12. The method of claim 1 , wherein the soluble ENPP1 polypeptide is a fusion protein comprising IgG Fc, wherein the Fc is fused to the C terminus of the soluble ENPP1 polypeptide.
13. The method of claim 1 , wherein said administering achieves a constant blood level of the polypeptide in the subject over time.
14. The method of claim 1 , wherein said administering occurs at a rate that replaces the amount of soluble ENPP1 that is metabolized and excreted from the body of the subject.