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 at least one disease selected from the group consisting of chronic kidney disease (CKD), end stage renal disease (ESRD), calcific uremic arteriolopathy (CUA), and calciphylaxis in a subject diagnosed with the at least one disease, the method comprising administering to the subject a therapeutically effective amount of a polypeptide comprising a soluble ecto-nucleotide pyrophosphate/phosphodiesterase-I (ENPP1) polypeptide, wherein the soluble ENPP1 polypeptide lacks a negatively-charged bone-targeting domain, whereby the at least one disease is reduced or its progression is prevented in the subject.
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 [NCBI#006199, SEQ ID NO: I].
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 sequence 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 ENPP2 signal sequence, 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 NPP2 (NCBI accession no. NP_001124335, 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 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 transmembrane domain and comprises a signal sequence, wherein the precursor polypeptide undergoes proteolytic processing to the soluble ENPP1 polypeptide.
8. The method of claim 1 , wherein the soluble ENPP1 polypeptide lacks a polyaspartic acid domain.
9. The method of claim 1 , wherein the polypeptide is administered locally, regionally, parenterally, systemically, acutely or chronically to the subject.
10. The method of claim 1 , wherein the subject is human.
11. The method of claim 1 , wherein the polypeptide is administered in a dosage range from about 0.01 and 50 mg/kg of body weight.
12. The method of claim 1 , wherein the polypeptide is administered in a dosage range from about 1 ng/kg and 500 mg/kg of body weight.
13. The method of claim 1 , wherein the polypeptide is administered daily to the subject.
14. The method of claim 1 , wherein the polypeptide is administered more than once per day to the subject.
15. The method of claim 1 , wherein the polypeptide is administered every other day to the subject.
16. The method of claim 1 , wherein the polypeptide is administered weekly or biweekly to the subject.
17. The method of claim 1 , wherein the polypeptide is administered monthly to the subject.
18. The method of claim 1 , wherein the polypeptide is administered to the subject as a pharmaceutical composition further comprising at least one excipient.
19. The method of claim 4 , wherein the signal sequence comprises NPP5 signal sequence or NPP7 signal sequence.
20. 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.
21. The method of claim 1 , wherein the soluble ENPP1 polypeptide is a fusion protein comprising a stability domain, wherein the stability domain is located at the C terminus of the ENPP1 polypeptide.
22. The method of claim 21 , wherein the stability domain is selected from a group consisting of albumin and IgG Fc.