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 - 28 . (canceled)
29 . A method for increasing extracellular pyrophosphate (PPi) levels in a subject having lower than normal extracellular PPi levels,
the method comprising administering to the subject a therapeutically effective amount of an isolated soluble ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) fusion polypeptide comprising PROTEIN fused to DOMAIN by a linker comprising 1-20 amino acids,
wherein the PROTEIN comprising an ENPP1 catalytic domain comprising residues 186-586 of SEQ ID NO: 1 and
wherein the DOMAIN is a human IgG Fc,
wherein the administering increases extracellular PPi levels in the subject.
30 . The method of claim 29 , wherein the linker connects the C-terminus of the PROTEIN with the N-terminus of the DOMAIN.
31 . The method of claim 29 , wherein the soluble ENPP1 fusion polypeptide lacks a negatively charged bone targeting sequence.
32 . The method of claim 29 , wherein the linker is a tripeptide.
33 . The method of claim 29 , wherein the linker is Leu-Ile-Asn (L I N).
34 . The method of claim 29 , wherein the DOMAIN is defined by the amino acid sequence set forth as SEQ ID NO: 26.
35 . The method of claim 29 , wherein the subject is a human.
36 . The method of claim 29 , wherein the subject is an infant.
37 . The method of claim 29 , wherein the subject suffers from a disease selected from the group consisting of Generalized Arterial Calcification of Infancy (GACI), Pseudoxanthoma elasticum (PXE), and calciphylaxis resulting from end stage renal disease.
38 . The method of claim 29 , wherein the subject has a loss of function mutation in ENPP1.
39 . The method of claim 29 , wherein the subject has a loss of function mutation in ATP-binding cassette sub-family C member 6 (ABCC6).
40 . The method of claim 29 , wherein the subject suffers from a disease selected from the group consisting of Ossification of the Posterior Longitudinal Ligament (OPLL), hypophosphatemic rickets, osteoarthritis, Chronic Kidney Disease (CKD), and calcification of atherosclerotic plaques.
41 . The method of claim 29 , wherein the ENPP1 fusion polypeptide is administered subcutaneously.
42 . The method of claim 29 , wherein the administering of the ENPP1 fusion polypeptide restores the subject's extracellular PPi levels within the range found in a subject not afflicted with GACI or PXE.
43 . The method of claim 29 , wherein the subject presents or is diagnosed with “failure to thrive”.
44 . The method of claim 29 , wherein the ENPP1 fusion polypeptide is administered daily to the subject.
45 . The method of claim 29 , wherein the ENPP1 fusion polypeptide is administered every other day to the subject.
46 . The method of claim 29 , wherein the ENPP1 fusion polypeptide is administered weekly, biweekly, or monthly to the subject.
47 . The method of claim 29 , wherein the ENPP1 fusion polypeptide is administered to the subject as a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient.
48 . The method of claim 29 , wherein the ENPP1 fusion polypeptide is administered to the subject as a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.