IP Library › Granted Patent US 12,247,046
Granted Patent B2
US 12,247,046 · App. 17/818,858 · Granted Mar 11, 2025

Ribonucleic acids with 4′-thio-modified nucleotides and related methods

Inventors: Frank DeRosa (Waltham, MA); Michael Heartlein (Waltham, MA)
Assignee: Translate Bio, Inc.
C07H21/02C12N15/67A61K9/1271A61K9/1272C12N2310/3515
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Quick Facts
Patent No.
US 12,247,046
App. No.
17/818,858
Granted
Mar 11, 2025
Kind
B2
Abstract

Disclosed are messenger RNA molecules and related compositions incorporating a 4′-thio modification in the furanose ring of at least one nucleotide residue, and methods of using these mRNAs to produce an encoded therapeutic protein in vivo and to treat or prevent diseases or disorders. In certain embodiments, the 4′-thio modified mRNA provides for enhanced stability and/or reduced immunogenicity in in vivo therapies.

Claims (18)

1. A lipid nanoparticle comprising:

at least one full-length mRNA molecule, wherein said full-length mRNA molecule has a coding region and, optionally, one or more non-coding regions,

encodes a full length protein, and

is at least 500 nucleotide residues in length, and

wherein 1%-20% of the total mRNA nucleotide residues of the full-length mRNA incorporate a 4′-thio-substituted furanose ring; and

wherein said lipid nanoparticle comprises a cationic lipid, a non-cationic lipid, a cholesterol-based lipid, and a PEGylated lipid; and

wherein said mRNA is encapsulated within said lipid nanoparticle.

2. The lipid nanoparticle of claim 1 , wherein the lipid nanoparticle comprises:

a non-cationic lipid selected from selected from DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleyl-sn-glycero-3-phosphoethanolamine), DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), and DOPG (2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol));

and

a cholesterol-based lipid that is cholesterol.

3. A method of producing a protein in vivo, comprising administering the lipid nanoparticle of claim 1 to a subject.

4. The method of claim 3 , wherein the method produces a therapeutic protein in vivo.

5. A pharmaceutical composition comprising the lipid nanoparticle of claim 1 .

6. The lipid nanoparticle of claim 1 , wherein the mRNA further comprises at least one nonstandard nucleotide residue.

7. The lipid nanoparticle of claim 6 , wherein the mRNA further comprises at least one nonstandard nucleotide residue selected from the group consisting of: 5-methyl-cytidine (“5mC”), pseudouridine (“ψU”), 2-thio-uridine (“2sU”), 5-methylcytosine, isocytosine, pseudoisocytosine, 5-bromouracil, 5-propynyluracil, 6-aminopurine, 2-aminopurine, inosine, diaminopurine, and 2-chloro-6-aminopurine cytosine.

8. The lipid nanoparticle of claim 6 , wherein the mRNA further comprises at least one nonstandard nucleotide residue having a sugar modification that is a 2′-O-alkyl modification.

9. The lipid nanoparticle of claim 8 , wherein the 2′-O-alkyl modification is a 2′-deoxy-2′-fluoro modification, a 2′-O-methyl modification, a 2′-O-methoxyethyl modification or a 2′-deoxy modification.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 25, 2022
From: DEROSA, FRANK; HEARTLEIN, MICHAEL
To: SHIRE HUMAN GENETIC THERAPIES, INC.
Reel/Frame 060894/0195 →
CHANGE OF NAME Recorded Aug 25, 2022
From: RANA THERAPEUTICS, INC.
To: TRANSLATE BIO, INC.
Reel/Frame 061232/0374 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 25, 2022
From: SHIRE HUMAN GENETIC THERAPIES, INC.
To: RANA THERAPEUTICS, INC.
Reel/Frame 061235/0202 →
Continuity (5)
Continuation 17032485 · Sep 25, 2020
Continuation 16282106 · Feb 21, 2019
Continuation 14776506
Provisional Application 61785098 · Mar 14, 2013
Related Publication 20230192753A1 · Jun 22, 2023
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