Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C12N-015/11
C07H-021/02
C12N-015/67
A61K-048/00
출원번호
US-0644072
(2012-10-03)
등록번호
US-9428535
(2016-08-30)
발명자
/ 주소
de Fougerolles, Antonin
Roy, Atanu
Schrum, Jason P.
Siddiqi, Suhaib
Hatala, Paul
Bancel, Stephane
출원인 / 주소
Moderna Therapeutics, Inc.
대리인 / 주소
Clark & Elbing LLP
인용정보
피인용 횟수 :
7인용 특허 :
377
초록
The present disclosure provides methods of increasing the level of a polypeptide of interest in a mammalian subject by administering a polynucleotide having one or more chemical modifications and a Protein:Cytokine ratio of greater than 100.
대표청구항▼
1. A method of expressing a polypeptide of interest in a mammalian subject comprising administering to said subject an isolated mRNA comprising: (a) a sequence of n number of linked nucleosides,(b) a 5′ UTR,(c) a 3′ UTR, and(d) at least one 5′ cap structure,wherein said isolated mRNA is fully modifi
1. A method of expressing a polypeptide of interest in a mammalian subject comprising administering to said subject an isolated mRNA comprising: (a) a sequence of n number of linked nucleosides,(b) a 5′ UTR,(c) a 3′ UTR, and(d) at least one 5′ cap structure,wherein said isolated mRNA is fully modified with 1-methylpseudouridine,wherein said isolated mRNA, when administered to peripheral blood mononuclear cells provides Protein:Cytokine (P:C) ratios of greater than 100 for TNF-alpha and greater than 100 for IFN-alpha after about eighteen or more hours, andwherein said P:C ratios are higher than those of a corresponding mRNA comprising pseudouridine in place of 1-methylpseudouridine. 2. The method of claim 1, wherein the isolated mRNA comprises a poly-A tail. 3. The method of claim 2, wherein the isolated mRNA is purified. 4. The method of claim 1, wherein the at least one 5′ cap structure is selected from the group consisting of Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine. 5. The method of claim 1, wherein the isolated mRNA is administered with a pharmaceutically acceptable excipient. 6. The method of claim 1, wherein the excipient is selected from a solvent, aqueous solvent, non-aqueous solvent, dispersion media, diluent, dispersion, suspension aid, surface active agent, isotonic agent, thickening or emulsifying agent, preservative, lipid, lipidoids liposome, lipid nanoparticle, core-shell nanoparticles, polymer, lipoplex, peptide, protein, cell, hyaluronidase, and mixtures thereof. 7. The method of claim 1, wherein the mRNA is formulated. 8. The method of claim 1, wherein the isolated mRNA is administered at a total daily dose of between 1 μg and 150 μg. 9. The method of claim 8, wherein administration is by injection. 10. The method of claim 8, wherein administration is intradermal or subcutaneous or intramuscular. 11. The method of claim 1, wherein levels of the polypeptide of interest in the serum of the mammal are at least 50 pg/mL at least two hours after administration. 12. The method of claim 11, wherein the levels of the polypeptide of interest in the serum of the mammal remain above 50 pg/mL for at least 72 hours after administration. 13. The method of claim 12, wherein the levels of the polypeptide of interest in the serum of the mammal remain above 60 pg/mL for at least 72 hours after administration. 14. The method of claim 1, wherein administration is in two or more equal or unequal split doses. 15. The method of claim 14, wherein the level of the polypeptide produced by the subject by administering split doses of the mRNA is greater than the levels produced by administering the same total daily dose of mRNA as a single administration. 16. The method of claim 1, wherein the mammalian subject is a human patient in need of an increased level of the polypeptide of interest. 17. The method of claim 16, wherein the increased level of the polypeptide of interest is detectable in a bodily fluid of said patient. 18. The method of claim 17, wherein the bodily fluid is selected from the group consisting of peripheral blood, serum, plasma, ascites, urine, cerebrospinal fluid (CSF), sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, cerumen, breast milk, broncheoalveolar lavage fluid, semen, prostatic fluid, cowper's fluid or pre-ejaculatory fluid, sweat, tears, cyst fluid, pleural and peritoneal fluid, pericardial fluid, lymph, chyme, chyle, bile, interstitial fluid, menses, pus, sebum, vomit, vaginal secretions, mucosal secretion, stool water, pancreatic juice, lavage fluids from sinus cavities, bronchopulmonary aspirates, blastocyl cavity fluid, and umbilical cord blood. 19. The method of claim 16, wherein administration is according to a dosing regimen which occurs over the course of hours, days, weeks, months, or years. 20. The method of claim 9, wherein injection is achieved by using one or more devices selected from multi-needle injection systems, catheter or lumen systems, and ultrasound, electrical or radiation based systems. 21. The method of claim 14, wherein the amount of mRNA administered in any dose is substantially equal. 22. The method of claim 14, wherein a first dose, a second dose or any of a plurality of doses are administered at substantially the same time. 23. The method of claim 1, wherein administration comprises a single unit dose between about 10 mg/kg and about 500 mg/kg. 24. The method of claim 1, wherein administration comprises a single unit dose between about 1.0 mg/kg and about 10 mg/kg. 25. The method of claim 1, wherein administration comprises a single unit dose between about 0.001 mg/kg and about 1.0 mg/kg.
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