Engineered nucleic acids and methods of use thereof

• US 9,181,319 B2
• Filed: 05/06/2014
• Issued: 11/10/2015
• Est. Priority Date: 08/06/2010
• Status: Active Grant

• Current Assignee: Moderna TX, Inc. (Moderna, Inc.)
• Original Assignee: Moderna Therapeutics, Inc. (Moderna, Inc.)
• Inventors: Schrum, Jason P., Bancel, Stephane, Afeyan, Noubar B.
• Primary Examiner(s): Nguyen, Quang
• Application Number:
  US14/270,736
• Publication Number:
  US 20140243399A1
• Time in Patent Office: 553 Days
• Field of Search: 536/23.51, 435/320.1
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/7115 Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/195 Chemokines, e.g. RANTES
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 48/0066 Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: A61K 48/0083 characterised by an aspect of the administration regime
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: C07K 14/685 Alpha-melanotropin

Abstract

Provided are compositions and methods for delivering biological moieties such as modified nucleic acids into cells to modulate protein expression. Such compositions and methods include the use of modified messenger RNAs, and are useful to treat or prevent diseases, disorders or conditions, or to improve a subject'"'"'s heath or wellbeing.

Claims

1. A pharmaceutical formulation comprising:

i) an effective amount of a messenger ribonucleic acid (mRNA) sequence encoding an insulin polypeptide, wherein the mRNA sequence is at least 95% identical to the sequence of SEQ ID NO;

23; and

ii) a pharmaceutically acceptable carrier,

wherein the formulation is suitable for repeated intravenous administration to a mammalian subject in need thereof.

2. The pharmaceutical formulation of claim 1, further comprising a lipid-based transfection reagent.

3. The pharmaceutical formulation of claim 1, wherein the effective amount of mRNA is selected from the group consisting of 100 ng, 250 ng, 500 ng, 1000 ng and 1500 ng.

4. A pharmaceutical formulation comprising:

i) an effective amount of an mRNA sequence encoding an insulin polypeptide, wherein the mRNA sequence is at least 95% identical to the sequence of SEQ ID NO;

23;

ii) a cell penetration agent; and

iii) a pharmaceutically acceptable carrier,

wherein the formulation is suitable for repeated intravenous administration to a mammalian subject in need thereof.

5. The pharmaceutical formulation of claim 4, further comprising a lipid-based transfection reagent.

6. The pharmaceutical formulation of claim 4, wherein the effective amount of mRNA is selected from the group consisting of 100 ng, 250 ng, 500 ng, 1000 ng and 1500 ng.

7. An mRNA sequence encoding an insulin polypeptide, wherein the mRNA sequence is at least 95% identical to the sequence of SEQ ID NO:

23.

8. The mRNA sequence of claim 7, wherein the mRNA sequence comprises pseudouridine and 5-methyl-cytidine.

9. The mRNA sequence of claim 8, wherein the mRNA sequence comprising pseudouridine and 5-methyl-cytidine is SEQ ID NO:

24.