Polynucleotides encoding relaxin
The invention relates to mRNA therapy for the treatment of fibrosis and/or cardiovascular disease. mRNAs for use in the invention, when administered in vivo, encode human relaxin, isoforms thereof, functional fragments thereof, and fusion proteins comprising relaxin. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of relaxin expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of toxic metabolites associated with deficient relaxin activity in subjects.
1. A method of treating a disorder associated with relaxin in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of an mRNA polynucleotide comprising an open reading frame (ORF) encoding a polypeptide comprising a relaxin protein, wherein the mRNA polynucleotide is formulated in an ionizable lipid nanoparticle, and wherein the ionizable lipid nanoparticle comprises an ionizable lipid of Compound 18 having the structure:
a salt or a stereoisomer thereof, or any combination thereof.
2. The method of claim 1 , wherein the method of treating the disorder associated with relaxin involves a single administration of the mRNA polynucleotide.
3. The method of claim 1 , wherein the method of treating the disorder associated with relaxin further comprises administering a weekly dose, a dose every two weeks, a dose every three weeks, or a dose every month.
4. The method of claim 1 , wherein the polypeptide is a relaxin fusion protein.
5. The method of claim 4 , wherein the relaxin fusion protein comprises an immunoglobulin (Ig) variable chain fragment.
6. The method of claim 1 , wherein the disorder associated with relaxin is selected from the group consisting of acute coronary syndrome with cardiac dysfunction, ischemia reperfusion associated with solid organ transplantation, cardiopulmonary bypass organ protection, chronic heart failure, acute heart failure, diabetic nephropathy, nonalcoholic steatohepatitis (NASH), atrial fibrillation, cardiac fibrosis, diabetic wound healing, and cirrhosis.
7. The method of claim 1 , wherein upon administration to the human subject the mRNA polynucleotide is in a dosage form that exhibits a pharmacokinetic (PK) profile comprising: a) a Tmax at about 30 to about 240 minutes after administration; and b) a plasma drug concentration plateau of at least 50% Cmax for a duration of about 60 to about 240 minutes, wherein the plasma drug is the polypeptide produced by the mRNA polynucleotide.
8. The method of claim 7 , wherein upon administration to the human subject the dosage form exhibits a PK profile wherein at least about 90% of the plasma drug is cleared from the plasma within about 5 to 7 days of the plasma drug concentration plateau.
9. The method of claim 1 , wherein upon administration to the human subject at least a 25% increase in circulating relaxin relative to baseline levels is achieved.
10. The method of claim 9 , wherein the circulating relaxin level is achieved for 2 hours up to 7 days.
11. The method of claim 1 , wherein the mRNA polynucleotide is present in a dosage of between 25 and 100 micrograms.
12. The method of claim 1 , wherein the method comprises administering to the human subject a single dosage of between 0.001 mg/kg and 0.005 mg/kg of the mRNA polynucleotide.
13. The method of claim 1 , wherein the relaxin protein comprises the amino acid sequence set forth in SEQ ID NO:1.
14. The method of claim 1 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:6.
15. A method of treating heart failure in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of an mRNA polynucleotide comprising an open reading frame (ORF) encoding a polypeptide comprising a relaxin protein, wherein the mRNA polynucleotide is formulated in an ionizable lipid nanoparticle, and wherein the ionizable lipid nanoparticle comprises an ionizable lipid of Compound 18 having the structure:
a salt or a stereoisomer thereof, or any combination thereof.
16. The method of claim 15 , wherein the method involves a single administration of the mRNA polynucleotide.
17. The method of claim 15 , wherein the method further comprises administering a weekly dose, a dose every two weeks, a dose every three weeks, or a dose every month.
18. The method of claim 15 , wherein the polypeptide is a relaxin fusion protein.
19. The method of claim 18 , wherein the relaxin fusion protein comprises an immunoglobulin (Ig) variable chain fragment.
20. The method of claim 15 , wherein upon administration to the human subject the mRNA polynucleotide is in a dosage form that exhibits a pharmacokinetic (PK) profile comprising: a) a Tmax at about 30 to about 240 minutes after administration; and b) a plasma drug concentration plateau of at least 50% Cmax for a duration of about 60 to about 240 minutes, wherein the plasma drug is the polypeptide produced by the mRNA polynucleotide.
21. The method of claim 20 , wherein upon administration to the human subject the dosage form exhibits a PK profile wherein at least about 90% of the plasma drug is cleared from the plasma within about 5 to 7 days of the plasma drug concentration plateau.
22. The method of claim 15 , wherein upon administration to the human subject at least a 25% increase in circulating relaxin relative to baseline levels is achieved.
23. The method of claim 22 , wherein the circulating relaxin level is achieved for 2 hours up to 7 days.
24. The method of claim 15 , wherein the mRNA polynucleotide is present in a dosage of between 25 and 100 micrograms.
25. The method of claim 15 , wherein the method comprises administering to the human subject a single dosage of between 0.001 mg/kg and 0.005 mg/kg of the mRNA polynucleotide.
26. The method of claim 15 , wherein the relaxin protein comprises the amino acid sequence set forth in SEQ ID NO:1.
27. The method of claim 15 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:6.