Polynucleotides encoding relaxin

Patent metadata

Field	Value
Publication number	US-10730924-B2
Application number	US-201816025302-A
Country	US
Kind code	B2
Filing date	Jul 2, 2018
Priority date	May 18, 2016
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

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.

First claim

What is claimed is:

1. A composition comprising an mRNA polynucleotide having an open reading frame encoding a polypeptide comprising at least one human relaxin protein formulated in an ionizable lipid nanoparticle, 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; and
wherein the relaxin protein is a relaxin fusion protein comprising an immunoglobulin (Ig) variable chain fragment.

2. The composition of claim 1 , wherein the Ig fragment comprises a variable light chain fragment.

3. The composition of claim 2 , wherein the variable light chain fragment comprises a VLκ IgG region.

4. The composition of claim 1 , wherein the relaxin protein comprises an amino acid sequence that is 70%-100% identical to the sequence of SEQ ID NO:1.

5. The composition of claim 1 , wherein the relaxin protein comprises an amino acid sequence that is 85%-100% identical to the sequence of SEQ ID NO:1.

6. The composition of claim 1 , wherein the composition is a unit dosage form having a dosage of 25 micrograms to 400 micrograms of the mRNA polynucleotide for a dose of up to 2 mg/kg in a human subject.

7. The composition of claim 1 , wherein the open reading frame is codon optimized.

8. The composition of claim 1 , wherein the mRNA comprises at least one chemical modification.

9. The composition of claim 8 , wherein the chemical modification is selected from pseudouridine, 1-methylpseudouridine, 1-ethyl pseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methoxyuridine and 2′-O-methyl uridine.

10. The composition of claim 1 , wherein the mRNA polynucleotide formulated in the ionizable lipid nanoparticle and administered by intravenous infusion or subcutaneous injection has a therapeutic index of greater than 60% of the therapeutic index of the mRNA polynucleotide alone.

11. The composition of claim 1 , wherein the mRNA polynucleotide formulated in the ionizable lipid nanoparticle and administered by intravenous infusion or subcutaneous injection has a therapeutic index of greater than 80% of the therapeutic index of the mRNA polynucleotide alone.

12. The composition of claim 1 , wherein the ionizable lipid nanoparticle comprises a molar ratio of about 20-60% ionizable lipid, about 5-25% non-cationic lipid, about 25-55% sterol, and about 0.5-15% PEG-modified lipid.

13. The composition of claim 1 , wherein the ionizable lipid nanoparticle has a polydispersity value of less than 0.4.

14. The composition of claim 1 , wherein the ionizable lipid nanoparticle has a net neutral charge at a neutral pH.

15. The composition of claim 1 , wherein the mRNA comprises at least one chemical modification and wherein the chemical modification is N1-methylpseudouridine.

16. The composition of claim 1 , wherein the relaxin protein comprises an amino acid sequence that is 90%-100% identical to the sequence of SEQ ID NO:1.

17. The composition of claim 1 , wherein the relaxin protein comprises an amino acid sequence that is 70%-100% identical to the sequence of SEQ ID NO:6.

18. The composition of claim 1 , wherein the relaxin protein comprises an amino acid sequence that is 85%-100% identical to the sequence of SEQ ID NO:6.

19. The composition of claim 1 , wherein the relaxin protein comprises an amino acid sequence that is 90%-100% identical to the sequence of SEQ ID NO:6.

20. The composition of claim 1 , wherein the mRNA polynucleotide comprises the open reading frame of SEQ ID NO:5.

21. The composition of claim 1 , wherein the mRNA polynucleotide comprises a polynucleotide sequence that is at least 95% identical to the sequence of SEQ ID NO:5.

Assignees

• Modernatx Inc

Inventors

• Ticho Barry
• Briancon-Eris Nadege
• Xia Zhinan
• Dousis Athanasios
• De Picciotto Seymour
• Presnyak Vladimir
• Hoge Stephen
• Mcfadyen Iain
• Benenato Kerry
• Kumarasinghe Ellalahewage Sathyajith

Classifications

• C07K2319/31

  fusions, other than Fc, for prolonged plasma life, e.g. albumin · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• C07K14/64 Primary

  Relaxins · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title