CFTR mRNA compositions and related methods and uses

• US 9,713,626 B2
• Filed: 10/06/2015
• Issued: 07/25/2017
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Ethris Gmbh, Translate Bio, Inc. (Sanofi )
• Original Assignee: Ethris Gmbh, RaNA Therapeutics Inc. (Sanofi )
• Inventors: Smith, Lianne, Rudolph, Carsten, Plank, Christian, DeRosa, Frank, Guild, Braydon Charles, Heartlein, Michael
• Primary Examiner(s): Chen, Shin Lin
• Application Number:
  US14/876,071
• Publication Number:
  US 20160106772A1
• Time in Patent Office: 658 Days
• Field of Search: 536 235, 536 241, 424450
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• 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 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/6935 the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
• 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 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07K 14/4712 Cystic fibrosis
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C12N 15/63 Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
• CPC Class Codes: C12N 15/88 using microencapsulation, e.g. using amphiphile liposome vesicle
• CPC Class Codes: C12N 9/14 Hydrolases (3)
• CPC Class Codes: C12Y 306/03049 : Channel-conductance-controlling ATPase (3.6.3.49)

Abstract

Pharmaceutical compositions comprising an mRNA-loaded nanoparticle, wherein the mRNA is an in vitro transcribed mRNA and has a coding sequence at least 80% identical to SEQ ID NO: 3, and wherein the mRNA encodes a human cystic fibrosis transmembrane conductance regulator (CFTR) protein comprising the amino acid sequence of SEQ ID NO:1 are provided. The present invention is particularly useful for treating cystic fibrosis.

Claims

1. A pharmaceutical composition comprising an mRNA-loaded nanoparticle,

wherein the mRNA is an in vitro transcribed mRNA and has a coding sequence at least 80% identical to SEQ ID NO:

3, and

wherein the mRNA encodes a human cystic fibrosis transmembrane conductance regulator (CFTR) protein comprising the amino acid sequence of SEQ ID NO;

1.

2. The pharmaceutical composition of claim 1, wherein the mRNA has the coding sequence at least 90% identical to SEQ ID NO:

3.

3. The pharmaceutical composition of claim 1, wherein the mRNA has the coding sequence 100% identical to SEQ ID NO:

3.

4. The pharmaceutical composition of claim 1, wherein the mRNA comprises a 5′

untranslated region (UTR) and/or a 3′

UTR.

5. The pharmaceutical composition of claim 4, wherein the 5′

-UTR comprises SEQ ID NO;

4 and/or the 3′

-UTR comprises SEQ ID NO;

5.

6. The pharmaceutical composition of claim 4, wherein the mRNA further comprises a poly-A tail.

7. The pharmaceutical composition of claim 6, wherein the poly-A tail is of at least 70, 100, 120, 150, 200, or 250 residues in length.

8. The pharmaceutical composition of claim 4, wherein the mRNA further comprises a 5′

cap.

9. The pharmaceutical composition of claim 1, wherein the mRNA comprises at least one nonstandard nucleobase.

10. The pharmaceutical composition of claim 9, wherein the nonstandard nucleobase is chosen from one or more of 5-methyl-cytidine, pseudouridine, and 2-thio-uridine.

11. The pharmaceutical composition of claim 1, wherein the composition is administered to the lung by aerosolization.

12. The pharmaceutical composition of claim 11 wherein the aerosolization is nebulization.

13. The pharmaceutical composition of claim 11, wherein the administration of the composition results in human CFTR protein expression in epithelial cells of the lung.

14. The pharmaceutical composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 1, wherein the nanoparticle comprises one or more organic cations.

16. The pharmaceutical composition of claim 15, wherein the one or more organic cations are selected from the group consisting of polyethyleneimine (PEI), protamine, PEGylated protamine, poly-L-lysine (PLL), PEGylated PLL, a cationic lipid and combinations thereof.

17. The pharmaceutical composition of claim 1, wherein the nanoparticle comprises a polymer.

18. The pharmaceutical composition of claim 17, wherein the polymer comprises branched PEI with a molecular weight ranging from 10 kDa to 40 kDa.

19. The pharmaceutical composition of claim 1, wherein the nanoparticle is a liposome.