Granted Patent B2

US 12,702,693 · App. 17/449,679 · Granted Aug 11, 2026

Inventors: Michael Heartlein (Lexington, MA); Frank DeRosa (Lexington, MA); Alan Kimura (Lexington, MA); Jonathan Abysalh (Lexington, MA); Anusha Dias (Lexington, MA); Shrirang Karve (Lexington, MA); Zarna Patel (Lexington, MA)

Assignee: TRANSLATE BIO, INC.

A61K38/1709A61K9/0078A61K9/127A61K48/0075A61P11/12C12N15/88

Abstract

Claims (20)

1 . A pharmaceutical composition comprising a lipid nanoparticle comprising one or more cholesterol-based lipid(s) at a molar ratio of greater than 30% of total lipid content and a PEG-modified lipid, wherein the lipid nanoparticle encapsulates an mRNA comprising an open reading frame encoding a human Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, wherein the mRNA is at a concentration of at least 0.6 mg/ml, wherein the composition further comprises one or more diluents selected from the group consisting of DMSO, ethylene glycol, glycerol, 2-Methyl-2,4-pentanediol (MPD), propylene glycol, sucrose, and trehalose, and wherein said composition is formulated for inhalation.

2 . The pharmaceutical composition of claim 1 , wherein, the lipid nanoparticle has a size less than 100 nm.

3 . The pharmaceutical composition of claim 1 , wherein the lipid nanoparticle comprises Cl2-200, DOTAP (1,2-diolelyl-3-trimethylammonium propane), DODAP (1,2-diolelyl-3-dimethylammonium propane), DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane), DlinDMA, DLin-KC2-DMA, HGT4003, or ICE ((3S, 10R, 13R, 17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 3-(1H-imidazol-4-yl)propanoate).

4 . The pharmaceutical composition of claim 1 , wherein the lipid nanoparticle comprises imidazole cholesterol ester (ICE).

5 . The pharmaceutical composition of claim 1 , wherein the mRNA encoding the CFTR protein further comprises a 5′ untranslated region (UTR) sequence of SEQ ID NO: 3.

6 . The pharmaceutical composition of claim 1 , wherein the mRNA encoding the CFTR protein further comprises a 3′ untranslated region (UTR) sequence of SEQ ID NO: 4 or SEQ ID NO: 5.

7 . The pharmaceutical composition of claim 1 , wherein the mRNA encoding the CFTR protein comprises a polynucleotide sequence at least 85%, at least 90% or at least 91% or at least 92% or at least 93% or at least 94% or at least 95% or at least 96% or at least 97% or at least 98% or at least 99% or 100% identical to SEQ ID NO: 6.

8 . The pharmaceutical composition of claim 1 , wherein the open reading frame of the mRNA encodes an amino acid sequence of SEQ ID NO: 2.

9 . The pharmaceutical composition of claim 1 , wherein the one or more cholesterol-based lipid(s) comprise(s) a cholesterol-based cationic lipid and/or cholesterol.

10 . The pharmaceutical composition of claim 1 , wherein the lipid nanoparticle further comprises one or more non-cationic lipids.

11 . The pharmaceutical composition of claim 10 , wherein the one or more non-cationic lipid(s) is distearoylphosphatidylcholine (“DSPC”); dioleoylphosphatidylcholine (“DOPC”); dipalmitoylphosphatidylcholine (“DPPC”); dioleoylphosphatidylglycerol (“DOPG”); dipalmitoylphosphatidylglycerol (“DPPG”); dioleoylphosphatidylethanolamine (“DOPE”); palmitoyloleoylphosphatidylcholine (“POPC”); palmitoyloleoyl-phosphatidylethanolamine (“POPE”); dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (“DOPE-mal”); dipalmitoyl phosphatidyl ethanolamine (“DPPE”); dimyristoylphosphoethanolamine (“DMPE”); distearoyl-phosphatidyl-ethanolamine (“DSPE”); phosphatidylserine; sphingolipids; cerebrosides; gangliosides; 16-O-monomethyl PE; 16-O-dimethyl PE; 18-1-trans PE; or 1-stearoyl-2-oleoyl-phosphatidyethanolamine (“SOPE”).

12 . The pharmaceutical composition of claim 11 , wherein the one or more non-cationic lipid(s) is DSPC.

13 . The pharmaceutical composition of claim 1 , wherein the lipid nanoparticle further comprises one or more cationic lipids.

14 . The pharmaceutical composition of claim 13 , wherein the one or more cationic lipid(s) is 1,2-diolelyl-3-trimethylammonium propane (“DOTAP”); 2-distearyloxy-N,N-dimethyl-3-aminopropane (“DSDMA”); 1,2-dioleyloxy-N,N-dimethyl-3-aminopropane (“DODMA”); 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane (“DLinDMA”); 1,2-dilinolenyloxy-N,N-dimethyl-3-aminopropane (“DLenDMA”); N-dioleyl-N,N-dimethylammonium chloride (“DODAC”); N,N-distearyl-N,N-dimethylarnrnonium bromide (“DDAB”); N-(1,2-dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl ammonium bromide (“DMRIE”); 3-dimethylamino-2-(cholest-5-en-3-beta-oxybutan-4-oxy)-1-(cis,cis-9,12-octadecadienoxy) propane (“CLinDMA”); 2-[5′-(cholest-5-en-3-beta-oxy)-3′-oxapentoxy)-3-dimethy 1-1-(cis,cis-9′,1-2′-octadecadienoxy) propane (“CpLinDMA”); N,N-dimethyl-3,4-dioleyloxybenzylamine (“DMOBA”); 1,2-N,N′-dioleylcarbamyl-3-dimethylaminopropane (“DOcarbDAP”); 2,3-Dilinoleoyloxy-N,N-dimethylpropylamine (“DLinDAP”); 1,2-N,N′-Dilinoleylcarbamyl-3-dimethylaminopropane (“DLincarbDAP”); 1,2-Dilinoleoylcarbamyl-3-dimethylaminopropane (“DLinCDAP”); 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (“DLin-K-DMA”); 2-((8-[(3P)-cholest-5-en-3-yloxy]octyl) oxy)-N, N-dimethyl-3-[(9Z, 12Z)-octadeca-9,12-dien-1-yloxy]propane-1-amine (“Octyl-CLinDMA”); (2R)-2-((8-[(3beta)-cholest-5-en-3-yloxy]octyl) oxy)-N, N-dimethyl-3-[(9Z, 12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine (“Octyl-CLinDMA (2R)”); (2S)-2-((8-[(3P)-cholest-5-en-3-yloxy]octyl) oxy)-N, fsl-dimethyh3-[(9Z, 12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine (“Octyl-CLinDMA (2S)”); 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (“DLin-K-XTC2-DMA”); or 2-(2,2-di ((9Z,12Z)-octadeca-9,12-dien-1-yl)-1,3-dioxolan-4-yl)-N,N-dimethylethanamine (“DLin-KC2-DMA”).

15 . The pharmaceutical composition of claim 14 , wherein the one or more cationic lipid(s) is DOTAP.

16 . The pharmaceutical composition of claim 1 , wherein the PEG-modified lipid is DMG-PEG 2000.

17 . The pharmaceutical composition of claim 1 , wherein the one or more cholesterol-based lipid(s) is cholesterol.

18 . The pharmaceutical composition of claim 1 , wherein the one or more diluent(s) is sucrose.

19 . A pharmaceutical composition comprising a lipid nanoparticle comprising one or more cholesterol-based lipid(s) at a molar ratio of greater than 30% of total lipid content, a PEG-modified lipid, one or more cationic lipid(s), and one or more non-cationic lipid(s), wherein the lipid nanoparticle encapsulates an mRNA comprising an open reading frame encoding a human Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, wherein the one or more cholesterol-based lipid(s) is cholesterol, wherein the PEG-modified lipid is DMG-PEG 2000, wherein the one or more non-cationic lipid(s) is DSPC, wherein the mRNA is at a concentration of at least 0.5 mg/mL, wherein the composition further comprises a diluent, wherein the diluent is sucrose, and wherein said composition is formulated for inhalation.

20 . A pharmaceutical composition comprising a lipid nanoparticle comprising one or more cholesterol-based lipid(s) at a molar ratio of greater than 30% of total lipid content, a PEG-modified lipid, one or more cationic lipid(s), and one or more non-cationic lipid(s), wherein the lipid nanoparticle encapsulates an mRNA comprising an open reading frame encoding a human Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, wherein the one or more cholesterol-based lipid(s) is cholesterol, wherein the PEG-modified lipid is DMG-PEG 2000, wherein the one or more non-cationic lipid(s) is DSPC, wherein the one or more cationic lipid(s) is DOTAP, wherein the mRNA is at a concentration of at least 3 mg/mL, wherein the composition further comprises a diluent, wherein the diluent is sucrose, and wherein said composition is formulated for inhalation.

Assignments (2)

Continuity (8)

References Cited (400)