Methods of improving cardiovascular function and treating cardiovascular disease using a recombinant ectonucleotide pyrophosphatase phosphodiesterase (NPP1)
The present invention provides methods for improving cardiovascular function in a human patient (e.g., reducing hypertension), as well as methods of treating a cardiovascular disease, by administering a recombinant human soluble ectonucleotide pyrophosphatase phosphodiesterase (hsNPP1), active fragment or fusion protein thereof.
1. A method for treating a human subject having hypertension, wherein said subject is not ENPP1 deficient, the method comprising administering to the subject one or more doses of a recombinant human soluble ectonucleotide pyrophosphatase phosphodiesterase (hsNPP1), active fragment or fusion protein thereof, wherein said administration reduces hypertension and said reduction in hypertension is independent of reduction in calcification in said subject.
2. A method for reducing hypertension in a human subject, wherein said subject is not ENPP1 deficient, the method comprising administering to the subject one or more doses of a recombinant human soluble ectonucleotide pyrophosphatase phosphodiesterase (hsNPP1), active fragment or fusion protein thereof, wherein said reduction in hypertension is independent of reduction in calcification in said subject.
3. The method of claim 1 or 2 , wherein the hsNPP1 is a fusion protein.
4. The method of claim 3 , wherein the fusion protein comprises an Fc region of an immunoglobulin.
5. The method of claim 3 , wherein the fusion protein comprises a targeting moiety.
6. The method of claim 5 , wherein said targeting moiety comprises at least eight consecutive aspartic acid or glutamic acid residues (SEQ ID NOs: 20 and 21, respectively).
7. The method of claim 3 , wherein the fusion protein comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO:11 or SEQ ID NO: 12.
8. The method of claim 1 or 2 , wherein the one or more doses contains 1.0 mg/kg (+/−20%) to 20.0 mg/kg (+/−20%) NPP1.
9. The method of claim 1 or 2 , wherein the one or more doses contains 1.0 mg/kg (+/−20%) to 5.0 mg/kg (+/−20%) NPP1.
10. The method of claim 1 or 2 , wherein the one or more doses is 0.2 mg/kg (+/−20%), 0.5 mg/kg (+/−20%), 1 mg/kg (+/−20%), 2.0 mg/kg (+/−20%), 5.0 mg/kg (+/−20%), 6.0 mg/kg (+/−20%), 10 mg/kg (+/−20%), 15 mg/kg (+/−20%), or 20 mg/kg (+/−20%).
11. The method of claim 1 or 2 , wherein two or more doses of NPP1 are administered at least 3 days, 1 week, 2 weeks or 1 month apart.
12. The method of claim 1 or 2 , wherein the administration is weekly, bi-weekly, or monthly.
13. The method of claim 1 or 2 , wherein the administration is intravenous, subcutaneous, or intraperitoneal.
14. The method of claim 1 or 2 , wherein an additional therapeutic agent is administered to the subject.
15. The method of claim 1 , wherein the treatment comprises a reduction in elevated blood pressure, normalization of blood pressure, a reduction in left ventricular end-diastolic pressure (EDP), a reduction in left ventricular end-systolic pressure (ESP), a reduction in ventricle stiffness, and/or an increase in contractility.
16. The method of claim 15 , wherein the reduction in elevated blood pressure is a reduction in blood pressure higher than 140 over 90 millimeters of mercury (mmHg) to 120 over 80 mm (+/−10%) of mercury (mmHg).
17. The method of claim 1 or 2 , wherein the one or more doses contains 1.0 mg/kg (+/−10%) to 20.0 mg/kg (+/−10%) NPP1.
18. The method of claim 1 or 2 , wherein the one or more doses contains 1.0 mg/kg (+/−5%) to 20.0 mg/kg (+/−5%) NPP1.
19. The method of claim 1 or 2 , wherein the one or more doses contains 1.0 mg/kg (+/−5%) to 20.0 mg/kg (+/−1%) NPP1.
20. The method of claim 1 or 2 , wherein the one or more doses contains 1.0 mg/kg (+/−10%) to 5.0 mg/kg (+/−10%) NPP1.
21. The method of claim 1 or 2 , wherein the one or more doses contains 1.0 mg/kg (+/−5%) to 5.0 mg/kg (+/−5%) NPP1.
22. The method of claim 1 or 2 , wherein the one or more doses contains 1.0 mg/kg (+/−1%) to 5.0 mg/kg (+/−1%) NPP1.
23. The method of claim 1 or 2 , wherein the one or more doses is 0.2 mg/kg (+/−10%), 0.5 mg/kg (+/−10%), 2.0 mg/kg 6.0 mg/kg (+/−10%), 10 mg/kg (+/−10%), or 15 mg/kg (+/−10%), or 20 mg/kg (+/−10%).
24. The method of claim 1 or 2 , wherein the one or more doses is 0.2 mg/kg (+/−5%), 0.5 mg/kg (+/−5%), 2.0 mg/kg (+/−5%), 6.0 mg/kg (+/−5%), 10 mg/kg (+/−5%), or 15 mg/kg (+/−5%).
25. The method of claim 1 or 2 , wherein the one or more doses is 0.2 mg/kg (+/−1%), 0.5 mg/kg (+/−1%), 2.0 mg/kg (+/−1%), 6.0 mg/kg (+/−1%), 10 mg/kg (+/−1%), or 15 mg/kg (+/−1%).