Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
First Claim
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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.
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Abstract
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.
876 Citations
25 Claims
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1. A method of expressing a polypeptide of interest in a mammalian subject comprising administering to said subject an isolated mRNA comprising:
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(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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)
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Specification